Michele Cascella

• Kersten, Flore; Cortés, Natalia Mojica; Serrano, Albert; Heim, Joel Benjamin; Guyette, Jessica L. & Cezar, Henrique Musseli [Show all 11 contributors for this article] (2026). A Single Amino Acid in the A2 Linker of Cholera Toxin Affects the Efficiency of Toxin Disassembly and Resulting Toxicity. ACS Omega. 11(38), p. 57763–57780. doi: 10.1021/acsomega.6c07022. Full text in Research Archive Show summary

  Abstract Cholera toxin (CT) from Vibrio cholerae and heat-labile enterotoxin (LT) from enterotoxigenic Escherichia coli are highly related AB5-type protein toxins that contain a catalytic A1 subunit, an A2 linker, and a cell-binding homopentamer of B subunits. The two proteins bind the same GM1 receptor and have similar levels of enzymatic activity toward their shared Gsα target, yet CT is more potent than LT. This difference has been mapped to a sequence of 11 amino acids (residues 226–236) near the C-terminus of the A2 linker. We now identify a single amino acid, aspartic acid at position 229, as a key contributor to the function of CT: substituting it for glutamic acid 229 from LT reduced the toxicity of CT to the level of LT. Toxin disassembly by protein disulfide isomerase (PDI), which is an essential event in the intoxication process, was less efficient for CTD229E and LT than for wild-type CT. This was further confirmed by a CT variant, in which four residues were converted into the LT sequence (D229E, I230V, T232I, and H233Y). To test our previous hypothesis that the positioning of the A1 subunit over the B pentamer critically determines toxin disassembly and thus potency, we determined crystal structures of both toxin variants to 1.6 Å resolution and calculated the angle at which the A2 linker exits the pore. The conformations of the two toxin chimeras lie between CT and LT, with the A2 C-terminus of the CT quadruple variant adopting essentially the same fold as LT. The A subunits of the toxin variants as well as that of LT showed a higher conformational freedom than CT as determined by molecular dynamics simulations, suggesting that a more rigid positioning of the A subunit drives toxin disassembly and potency. Our collective data uncover the critical role of D229 in toxin folding and structural dynamics, which in turn impacts toxin potency through effects on the efficiency of PDI-driven toxin disassembly.

• Cezar, Henrique Musseli; Berton, Giacomo; Lorenzetto, Tommaso; Zorzi, Sandro; Foumthuim, Cedrix J. Dongmo & Szostak, Szymon Mikolaj [Show all 15 contributors for this article] (2026). Self-Assembly of Unconventional Triphenylene-Based Frustrated Amphiphile in Solution. Langmuir. ISSN 0743-7463. 42(6), p. 4507–4517. doi: 10.1021/acs.langmuir.5c05203. Full text in Research Archive Show summary

  Unconventional amphiphilic molecules having a rigid hydrophobic central unit and flexible or semiflexible hydrophilic chains on the rim have proven valuable in several technological applications, for example, host–guest chemistry. The further presence of alternating hydrophobic and hydrophilic tails complicates the definition of clear core and shell regions, resulting in complex segregation and frustrated self-assembly. In this study, we investigate symmetric triphenylene-based amphiphilic derivatives with alternating benzyl and alkylsulfonate groups. We characterize their self-assembly in water and different solutions using several experimental techniques, including NMR, atomic force microscopy, dynamic light scattering, and small-angle X-ray and neutron scattering, alongside extensive molecular dynamics simulations, including both atomistic and coarse-grained integrative modeling with metainference. In aqueous solutions, these amphiphiles form stacked assemblies, adopting alternate up–down conformations driven by π-stacking of up to six molecules. The introduction of NaCl salt screens unfavorable electrostatic interactions, thus promoting further π-stacking and leading to the formation of larger elongated aggregates.

• Bortoli, Marco; Bore, Sigbjørn Løland; Eisenstein, Odile & Cascella, Michele (2025). The influence of the organic residue and the solvent in the Schlenk equilibrium for Grignard reagents in THF. A molecular dynamics study with machine learning potentials. Journal of Catalysis. ISSN 0021-9517. 454. doi: 10.1016/j.jcat.2025.116619. Full text in Research Archive Show summary

  The Schlenk equilibrium is an essential characteristic of the Grignard reagents. However, its quantitative aspects remain poorly understood. In this work, we perform molecular dynamics simulations to characterise how the Schlenk reaction is affected by varying the alkyl R groups (Me, Et, i-Pr, t-Bu). For each R group, the reactivity profiles were obtained through enhanced sampling on fully solvated dinuclear species, leveraging a newly developed machine learning potential trained on ab initio data. While the topologies of the Helmholtz energy maps are qualitatively similar, the energy ranges vary significantly with the R groups. Bulkier R groups disfavour higher solvation of the magnesium centre, with direct implications for the activation and mechanism of the Schlenk exchange. With respect to dichloro-bridged species, the concentrations of monochloro-bridged and separated species increase with the size of R and the degree of solvation. The energy barrier for ligand exchange increases with the size of R, and it is particularly noticeable for R = t-Bu, in agreement with experimental data. As excess solvation of one of the magnesium centres is associated with the most important reaction pathways, it can be deduced that early formation of monochloro-bridged species favours the Cl/R exchange, especially for large R groups. The formation of these species is favoured by higher Mg solvation for small R groups, and by the steric volume of R itself for large R, pointing at a constructive effect of the solvent and R promoting Cl/R exchange. Our study shows that a full characterisation of the speciation of Grignard reagents in solution is possible at reasonable computational costs with machine-learning potentials.

• Ahmad, Ahmad Ali; Mors, Mira; Carrer, Manuel; Li, Xinmeng; Bilokapić, Silvija & Halić, Mario [Show all 8 contributors for this article] (2025). Structure and dynamics of 2x(CENP-A/H4)2 octasome reveal a possible intermediate in centromeric chromatin. Life Science Alliance (LSA). 9(3). doi: 10.26508/lsa.202503377. Full text in Research Archive Show summary

  The centromere is a part of the chromosome that is essential for the even segregation of duplicated chromosomes during cell division. It is epigenetically defined by the presence of the histone H3 variant CENP-A. CENP-A associates specifically with a group of 16 proteins that form the constitutive centromere-associated network (CCAN) of proteins. In mitosis, the kinetochore forms on the CCAN to connect the duplicated chromosomes to the microtubules protruding from the cell poles. Previous studies have shown that CENP-A replaces H3 in nucleosomes, and recently, the structures of CENP-A-containing nucleosomes in complex with CCANs have been revealed, but they show only a limited interaction between CCANs and CENP-A. Here, we report the cryo-EM structure of 2x(CENP-A/H4)2 octasomes assembled on DNA in the absence of H2A/H2B histone dimer and speculate how (CENP-A/H4)2 tetrasomes might serve as a platform for CCAN organization.

• Koynarev, Vladimir Rosenov; Nader, Manuela Leal; Borgos, Kari Kristine Almåsvold; Cezar, Henrique Musseli; Narayanan, Theyencheri & Porcar, Lionel [Show all 8 contributors for this article] (2025). Structural pores not required: Antimicrobial peptides induce ion permeabilization of lipid membranes through transient water channels. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 122(44). doi: 10.1073/pnas.2517944122. Full text in Research Archive Show summary

  Antimicrobial peptides (AMPs) are highly potent and broad-spectrum antibiotics, found as components of the innate immune system in almost all forms of life. Despite being commonly accepted that the mechanism of action of AMPs is associated with the permeabilization of the cell membrane, the structural and dynamical means by which this occurs are still heavily debated. In this work, we employ experimental time-resolved small angle X-ray scattering to follow in real time the AMP-induced ion transport in lipid vesicles, while simultaneously resolving the membrane structure and peptide partitioning. For several natural AMPs, we show that they can effectively permeabilize the lipid membrane despite only binding peripherally to the outer membrane leaflet. Our experiments reveal rapid ion transport associated with AMP binding, yielding salt equilibration in a few tens of milliseconds, while not detecting evidence of transversal and structurally stable peptide pores. On the contrary, new analysis of previously reported all-atom molecular dynamics simulations shows that lipid flip-flop, accelerated by the peripherally bound peptides, leads to the formation of transient, ion-conducting water channels. A corresponding diffusional model indicates that such short-lived, transient pores explain the observed ion transport better than stable pores.

• Manasi, Iva; Bortoli, Marco; Bowron, Daniel T.; Campana, Mario; Hammond, Oliver S. & Headen, Thomas F. [Show all 11 contributors for this article] (2025). Are Grignard Reactions in Deep Eutectic Solvents Interface‐Driven? Angewandte Chemie International Edition. ISSN 1433-7851. 64(42). doi: 10.1002/anie.202513649. Full text in Research Archive Show summary

  Due to their high reactivity, organolithium and organomagnesium addition to ketones is usually performed under inert atmosphere at low temperature. Recent work has shown that, by dissolving the substrate in deep eutectic solvents (DES), these processes can be carried out on the benchtop, in air at room temperature. Surprisingly, the organometallic reagent, added to the DES from an organic solution, works in these conditions and gives better yields than in the standard setup. Here, we investigated acetophenone in a (1:2) choline chloride:glycerol (ChCl:Gly) DES solution by experimental liquid diffraction, neutron reflectometry, NMR, interfacial tension measurements, and by computational modelling. Our data show that this DES is a poor solvent for the ketone and promotes its accumulation at the surface of the liquid or its escape into the organic solvent. Molecular dynamics simulations of Grignard reagent i ‐PrMgCl in the (ChCl:Gly)/tetrahydrofuran biphasic system indicate also preference for its localisation at the interface. These results pinpoint why this combination of solvents promote the reaction, require stirring, and accounts for the lack of rapid decomposition of the organometallic reagents.

• Rio, Jordan; Pessemesse, Quentin; Cascella, Michele; Payard, Pierre-Adrien & Perrin, Marie-Eve L. (2025). Organozinc Reagents in Solution: Insights from Ab Initio Molecular Dynamics and X-ray Absorption Spectroscopy. Inorganic Chemistry. ISSN 0020-1669. 64(30), p. 15774–15782. doi: 10.1021/acs.inorgchem.5c02580. Full text in Research Archive Show summary

  Organozinc reagents are widely used in synthesis; however, their solution-phase structures and the resulting effects on reactivity remain insufficiently understood. Here, we present a computational workflow, validated by X-ray absorption spectroscopy, to characterize the solvation dynamics of ZnCl2, ZnMeCl, and ZnMe2 in tetrahydrofuran (THF) solution. Ab initio molecular dynamics (metadynamics and Blue Moon sampling) in explicit solvent cage reveal a distribution of solvation states at room temperature, resolving the long-standing ambiguity surrounding the solvation environment of ZnMe2. Spectral signatures derived from molecular dynamic trajectories and time-dependent DFT closely match the experimental XANES and IR data collected from the literature. We apply this framework to evaluate the effects of solvation on the transmetalation between ZnMe2 and PdMeCl(PPh2Me)2. Although THF coordination to ZnMe2 has a limited influence on activation barriers, changes in solvation state along the reaction coordinate emerge as key thermodynamic drivers. These findings underscore the need to account for solvation equilibria when modeling organozinc-mediated catalytic processes.

• Cascella, Michele; Bore, Sigbjørn Løland & Eisenstein, Odile (2025). The fellowship of the Grignard: 21st century computational tools for hundred-year-old chemistry. Chemical Science. ISSN 2041-6520. 16, p. 8196–8216. doi: 10.1039/d5sc01078k. Full text in Research Archive Show summary

  This perspective begins with the discovery of the Grignard reaction by a graduate student in the last years of the 19th century, followed by describing why it has remained largely unexplained for more than a century. From the summary of what has been achieved, focusing on the computational aspects, it is now clear that further studies of the chemistry of any chemical species that is highly sensitive to solvents, such as Group I and II elements, require a holistic approach that includes the solute and the solvent together. Ab initio molecular dynamics, which meets these requirements, has produced some results but has hit hard limits due to its relatively high computational costs. In these days, it is becoming clear that data-driven methods, including machine learning potentials and simulations driven by quantitative on-the-fly calculation of relevant observables, have the potential to better and more completely explore the very large chemical space associated with the presence of a large number of species in solution. These methodologies have the chance to give the keys to enter the challenging and still poorly explored world of chemical species whose behaviour and reactivity are strongly influenced by the solvent and the experimental conditions.

• Carrer, Manuel; Cezar, Henrique Musseli; Bore, Sigbjørn Løland; Ledum, Morten & Cascella, Michele (2024). Learning Force Field Parameters from Differentiable Particle-Field Molecular Dynamics. Journal of Chemical Information and Modeling. ISSN 1549-9596. 64, p. 5510–5520. doi: 10.1021/acs.jcim.4c00564. Full text in Research Archive Show summary

  We develop ∂-HylleraasMD (∂-HyMD), a fully end-to-end differentiable molecular dynamics software based on the Hamiltonian hybrid particle-field formalism, and use it to establish a protocol for automated optimization of force field parameters. ∂-HyMD is templated on the recently released HylleraaasMD software, while using the JAX autodiff framework as the main engine for the differentiable dynamics. ∂-HyMD exploits an embarrassingly parallel optimization algorithm by spawning independent simulations, whose trajectories are simultaneously processed by reverse mode automatic differentiation to calculate the gradient of the loss function, which is in turn used for iterative optimization of the force-field parameters. We show that parallel organization facilitates the convergence of the minimization procedure, avoiding the known memory and numerical stability issues of differentiable molecular dynamics approaches. We showcase the effectiveness of our implementation by producing a library of force field parameters for standard phospholipids, with either zwitterionic or anionic heads and with saturated or unsaturated tails. Compared to the all-atom reference, the force field obtained by ∂-HyMD yields better density profiles than the parameters derived from previously utilized gradient-free optimization procedures. Moreover, ∂-HyMD models can predict with good accuracy properties not included in the learning objective, such as lateral pressure profiles, and are transferable to other systems, including triglycerides.

• Sen, Samiran; Cezar, Henrique Musseli; Ledum, Morten; Li, Xinmeng & Cascella, Michele (2024). Phase Coexistence in Hamiltonian Hybrid Particle-Field Theory Using a Multi-Gaussian Approach. Journal of Physical Chemistry B. ISSN 1520-6106. 128(47), p. 11739–11747. doi: 10.1021/acs.jpcb.4c05525. Full text in Research Archive Show summary

  This study introduces an implementation of multiple Gaussian filters within the Hamiltonian hybrid particle-field (HhPF) theory, aimed at capturing phase co-existence phenomena in mesoscopic molecular simulations. By employing a linear combination of two Gaussians, we demonstrate that HhPF can generate potentials with attractive and steric components analogous to Lennard-Jones potentials, which are crucial for modeling phase co-existence. We compare the performance of this method with the Multi-Gaussian Core Model (MGCM) in simulating liquid-gas coexistence for a single-component system across various densities and temperatures. Our results show that HhPF effectively captures detailed information on phase co-existence and interfacial phenomena, including micro-configuration transitions and increased interfacial fluctuations at higher temperatures. Notably, the phase boundaries obtained from HhPF simulations align more closely with those of Lennard-Jones systems compared to the MGCM results. This work advances the hybrid particle-field methodology to address phase co-existence without requiring modifications to the equation of state or introducing additional interaction energy functional terms, offering a promising approach for mesoscale molecular simulations of complex systems.

• Kang, Bong Joo; Rohwer, Egmont J.; Rohrbach, David; Zyaee, Elnaz; Akbarimoosavi, Maryam & Ollmann, Zoltan [Show all 14 contributors for this article] (2024). Time-resolved THz Stark spectroscopy of molecules in solution. Nature Communications. 15(1). doi: 10.1038/s41467-024-48164-w. Full text in Research Archive Show summary

  For decades, it was considered all but impossible to perform Stark spectroscopy on molecules in a liquid solution, because their concomitant orientation to the applied electric field results in overwhelming background signals. A way out was to immobilize the solute molecules by freezing the solvent. While mitigating solute orientation, freezing removes the possibility to study molecules in liquid environments at ambient conditions. Here we demonstrate time-resolved THz Stark spectroscopy, utilizing intense single-cycle terahertz pulses as electric field source. At THz frequencies, solute molecules have no time to orient their dipole moments. Hence, dynamic Stark spectroscopy on the time scales of molecular vibrations or rotations in both non-polar and polar solvents at arbitrary temperatures is now possible. We verify THz Stark spectroscopy for two judiciously selected molecular systems and compare the results to conventional Stark spectroscopy and first principle calculations.

• Cezar, Henrique Musseli; Bjørnestad, Victoria Ariel; Prévost, Sylvain François; Lund, Reidar & Cascella, Michele (2024). Beyond Core–Shell Micellar Structures: Complex Structures in Simple Surfactants. Small Structures. doi: 10.1002/sstr.202400553. Full text in Research Archive Show summary

  Small-angle X-ray/neutron scattering (SAXS/SANS) techniques provide valuable nanostructural information of self-assembling molecules. However, extracting the information from these experiments can be a challenging task, usually relying on predetermined assumptions. Conventional models for surfactant micelles consider a core–shell structure with a hydrophobic tail encapsulated by the hydrophilic part. This approach is successful in many cases but can fail even for common surfactants such as Triton X-100 (TX-100). SAXS and SANS combined with Metainference molecular simulations are employed to investigate TX-100 assemblies, showing how more complex models, with diffuse core–shell boundaries, multilayering, and polydispersity, are needed to explain the aggregation. This is the first time that Metainference is employed with SAXS and SANS simultaneously to obtain the structural ensemble of assemblies. Compared to regular micelles formed by chemically similar C12EO10 molecules, the role of the hydrophobic core in micellization is discussed, finding that the relatively shorter and less hydrophobic tail of TX-100 favors polymorphism.

• Giovanetti, Marinella de; Eliasson, Sondre Hilmar Hopen; Bore, Sigbjørn Løland; Eisenstein, Odile & Cascella, Michele (2024). Morphology of lithium halides in tetrahydrofuran from molecular dynamics with machine learning potentials. Chemical Science. ISSN 2041-6520. doi: 10.1039/d4sc04957h. Full text in Research Archive Show summary

  The preferred structures of lithium halides (LiX, with X = Cl, Br, I) in organic solvents have been the subject of a wide scientific debate, and a large variety of forms has been isolated and characterized by X-ray diffraction. The identified molecular scaffolds for LiX are diverse, often built on (LiX)n rings with a prevalence of rhomboidal arrangements and an appropriate number of solvent or Lewis base molecules coordinating the lithium ions. Much less is known about the structures of LiX in solution, limiting the understanding of the synergistic role of LiX in reactions with various organometallic complexes, as prominently represented by the turbo Grignard reaction. Here, we trained a machine learning potential on ab initio data to explore the complex conformational landscape for systems comprising four LiX moieties in tetrahydrofuran (THF). For all the considered halogens a large number of scaffolds were found at thermally accessible free energy values, indicating that LiX in solution are a diverse ensemble constituted of (LiX)n moieties of various sizes, completed by the appropriate number of coordinating THF. LiCl shows a preference for compact, pseudo-cubane Li4Cl4(THF)4 structures, coexisting with open rings. At concentrations close to the solubility limit, LiCl forms hexagonal structures, in analogy with literature observations on pre-nucleating NaCl. LiBr tends to favour less compact, more solvated aggregates. LiI significantly differs from the two other cases, producing highly solvated, monomeric, dimeric, or linear structures. This study provides a comprehensive view of LiX in organic solvent, revealing dynamical polymorphism that is not easily observable experimentally.

• Sen, Samiran; Cezar, Henrique Musseli; Ledum, Morten; Li, Xinmeng & Cascella, Michele (2024). Phase coexistence in Hamiltonian hybrid particle--field theory using a Multi-Gaussian approach. ChemRxiv. ISSN 2573-2293. doi: 10.26434/chemrxiv-2024-cm4xr-v2. Full text in Research Archive
• Giovanetti, Marinella de; Eliasson, Sondre Hilmar Hopen; Bore, Sigbjørn Løland; Eisenstein, Odile & Cascella, Michele (2024). Morphology of Lithium Halides in Tetrahydrofuran from Molecular Dynamics with Machine Learning Potentials. ChemRxiv. ISSN 2573-2293. doi: 10.26434/chemrxiv-2024-mxjqn. Full text in Research Archive
• Giovanetti, Marinella de; Eliasson, Sondre Hilmar Hopen; Castro, Abril C; Eisenstein, Odile & Cascella, Michele (2023). Morphological Plasticity of LiCl Clusters Interacting with Grignard Reagent in Tetrahydrofuran. Journal of the American Chemical Society. ISSN 0002-7863. 145(30), p. 16305–16309. doi: 10.1021/jacs.3c04238. Full text in Research Archive Show summary

  Ab initio molecular dynamics simulations are used to explore tetrahydrofuran (THF) solutions containing pure LiCl and LiCl with CH3MgCl, as model constituents of the turbo Grignard reagent. LiCl aggregates as Li4Cl4, which preferentially assumes compact cubane-like conformations. In particular, an open-edge pseudotetrahedral frame is promoted by solvent-assisted Li–Cl bond cleavage. Among the Grignard species involved in the Schlenk equilibrium, LiCl prefers to coordinate MgCl2 through μ2-Cl bridges. Using a 1:1 Li:Mg ratio, the plastic tetranuclear LiCl cluster decomposes to a highly solvated mixed LiCl·MgCl2 aggregate with prevalent Li–(μ2-Cl)2–Mg rings and linear LiCl entities. The MgCl2-assisted disaggregation of Li4Cl4 occurs through transient structures analogous to those detected for pure LiCl in THF, also corresponding to moieties observed in the solid state. This study identifies a synergistic role of LiCl for the determination of the compounds present in turbo Grignard solutions. LiCl shifts the Schlenk equilibrium promoting a higher concentration of dialkylmagnesium, while decomposing into smaller, more soluble, mixed Li:Mg:Cl clusters.

• Ledum, Morten; Sen, Samiran; Li, Xinmeng; Carrer, Manuel; Feng, Yu & Cascella, Michele [Show all 7 contributors for this article] (2023). HylleraasMD: A Domain Decomposition-Based Hybrid Particle-Field Software for Multiscale Simulations of Soft Matter. Journal of Chemical Theory and Computation. ISSN 1549-9618. doi: 10.1021/acs.jctc.3c00134. Full text in Research Archive Show summary

  We present HylleraasMD (HyMD), a comprehensive implementation of the recently proposed Hamiltonian formulation of hybrid particle-field molecular dynamics. The methodology is based on a tunable, grid-independent length-scale of coarse graining, obtained by filtering particle densities in reciprocal space. This enables systematic convergence of energies and forces by grid refinement, also eliminating nonphysical force aliasing. Separating the time integration of fast modes associated with internal molecular motion from slow modes associated with their density fields, we enable the first time-reversible, energy-conserving hybrid particle-field simulations. HyMD comprises the optional use of explicit electrostatics, which, in this formalism, corresponds to the long-range potential in particle-mesh Ewald. We demonstrate the ability of HyMD to perform simulations in the microcanonical and canonical ensembles with a series of test cases, comprising lipid bilayers and vesicles, surfactant micelles, and polypeptide chains, comparing our results to established literature. An on-the-fly increase of the characteristic coarse-grain length significantly speeds up dynamics, accelerating self-diffusion and leading to expedited aggregation. Exploiting this acceleration, we find that the time scales involved in the self-assembly of polymeric structures can lie in the tens to hundreds of picoseconds instead of the multimicrosecond regime observed with comparable coarse-grained models.

• Bjørnestad, Victoria Ariel; Li, Xinmeng; Tribet, Christophe; Lund, Reidar & Cascella, Michele (2023). Micelle kinetics of photoswitchable surfactants: Self-assembly pathways and relaxation mechanisms. Journal of Colloid and Interface Science. ISSN 0021-9797. 646, p. 883–899. doi: 10.1016/j.jcis.2023.05.057. Full text in Research Archive Show summary

  Hypothesis: A key question in the kinetics of surfactant self-assembly is whether exchange of unimers or fusion/fission of entire micelles is the dominant pathway. In this study, an isomerizable surfactant is used to explore fundamental out-of-equilibrium kinetics and mechanisms for growth and dissolution of micelles. Experiments: The kinetics of cationic surfactant 4-butyl-4'-(3-trimethylammoniumpropoxy)-phenylazobenzene was studied using molecular dynamics simulations. The fusion and exchange processes were investigated using umbrella sampling. Equilibrium states were validated by comparison with small-angle X-ray scattering data. The photo-isomerization event was simulated by modifying the torsion potential of the photo-responsive group to emulate the trans-to-cis transition. Findings: Micelle growth is dominated by unimer exchange processes, whereas, depending on the conditions, dissolution can occur both through fission and unimer expulsion. Fusion barriers increase steeply with the aggregation number making this an unlikely pathway to equilibrium for micelles of sizes that fit with the experimental data. The barriers for unimer expulsion remain constant and are much lower for unimer insertion, making exchange more likely at high aggregation. When simulating photo-conversion events, both fission and a large degree of unimer expulsion can occur depending on the extent of the out-of-equilibrium stress that is put on the system.

• Pena, Dario Segura; Hovet, Oda; Gogoi, Hemanga; Dawicki-Mckenna, Jennine; Wøien, Stine Malene Hansen & Carrer, Manuel [Show all 9 contributors for this article] (2023). The structural basis of the multi-step allosteric activation of Aurora B kinase. eLIFE. 12. doi: 10.7554/eLife.85328. Full text in Research Archive Show summary

  Aurora B, together with IN-box, the C-terminal part of INCENP, forms an enzymatic complex that ensures faithful cell division. The [Aurora B/IN-box] complex is activated by autophosphorylation in the Aurora B activation loop and in IN-box, but it is not clear how these phosphorylations activate the enzyme. We used a combination of experimental and computational studies to investigate the effects of phosphorylation on the molecular dynamics and structure of [Aurora B/IN-box]. In addition, we generated partially phosphorylated intermediates to analyze the contribution of each phosphorylation independently. We found that the dynamics of Aurora and IN-box are interconnected, and IN-box plays both positive and negative regulatory roles depending on the phosphorylation status of the enzyme complex. Phosphorylation in the activation loop of Aurora B occurs intramolecularly and prepares the enzyme complex for activation, but two phosphorylated sites are synergistically responsible for full enzyme activity.

• Carrer, Manuel; Nielsen, Josefine Eilsø; Cezar, Henrique Musseli; Lund, Reidar; Cascella, Michele & Silva, Thereza Amelia Soares da (2023). Accelerating Lipid Flip-Flop at Low Concentrations: A General Mechanism for Membrane Binding Peptides. The Journal of Physical Chemistry Letters. 14(31), p. 7014–7019. doi: 10.1021/acs.jpclett.3c01284. Full text in Research Archive Show summary

  We report a physicochemical investigation of the lipid transport properties of model lipid membranes in the presence of the antimicrobial peptide indolicidin through comparisons of experimental SANS/SAXS scattering techniques to fully atomistic molecular dynamics simulations. In agreement with the experiment, we show that upon peripheral binding of the peptides, even at low concentrations, lipid flip-flop dynamics is greatly accelerated. Computer modeling elucidates the interplay between structural changes and lipid dynamics induced by peptides and proposes a mechanism for the mode of action of antimicrobial peptides, assessing the major role of entropy for the catalysis of the flipping events. The mechanism introduced here is universal for all peptides with preferential peripheral binding to the membrane as it does not depend on the specific amino acid sequence.

• Cezar, Henrique Musseli & Cascella, Michele (2023). SANS Spectra with PLUMED: Implementation and Application to Metainference. Journal of Chemical Information and Modeling. ISSN 1549-9596. 63(16), p. 4979–4985. doi: 10.1021/acs.jcim.3c00724. Full text in Research Archive Show summary

  Using small-angle scattering with either X-ray or neutron sources has become common in the investigation of soft-matter systems. These experiments provide information about the coarse shape of the scattered objects, but obtaining more-detailed information can usually only be achieved with the aid of molecular simulations. In this Application Note, we report the implementation of an extension in PLUMED to compute the small-angle neutron scattering (SANS), which can be used for data processing as well for enhanced sampling, in particular with the metainference method to bias simulations and sample structures with a resulting spectrum in agreement with an experimental reference. Our implementation includes a resolution function that can be used to smear the SANS intensities according to beamline error sources and is compatible with both all-atom and coarse-grained simulations. Scripts to aid in the calculation of the scattering lengths when the system is coarse-grained and to aid in preparing the inputs are provided. We illustrate the use of the implementation with metainference by performing coarse-grained simulations of beta-octylglucoside and dodecylphosphocholine micelles in water. With different software and different Hamiltonians, we show that the metainference SANS bias can drive micelles to be split and to change shapes to achieve a better agreement with the experimental reference.

• Sen, Samiran; Ledum, Morten; Bore, Sigbjørn Løland & Cascella, Michele (2023). Soft Matter under Pressure: Pushing Particle-Field Molecular Dynamics to the Isobaric Ensemble. Journal of Chemical Information and Modeling. ISSN 1549-9596. 63, p. 2207–2217. doi: 10.1021/acs.jcim.3c00186. Full text in Research Archive Show summary

  Hamiltonian hybrid particle–field molecular dynamics is a computationally efficient method to study large soft matter systems. In this work, we extend this approach to constant-pressure (NPT) simulations. We reformulate the calculation of internal pressure from the density field by taking into account the intrinsic spread of the particles in space, which naturally leads to a direct anisotropy in the pressure tensor. The anisotropic contribution is crucial for reliably describing the physics of systems under pressure, as demonstrated by a series of tests on analytical and monatomic model systems as well as realistic water/lipid biphasic systems. Using Bayesian optimization, we parametrize the field interactions of phospholipids to reproduce the structural properties of their lamellar phases, including area per lipid, and local density profiles. The resulting model excels in providing pressure profiles in qualitative agreement with all-atom modeling, and surface tension and area compressibility in quantitative agreement with experimental values, indicating the correct description of long-wavelength undulations in large membranes. Finally, we demonstrate that the model is capable of reproducing the formation of lipid droplets inside a lipid bilayer.

• Castro, Abril C; Cascella, Michele; Perutz, Robin N.; Raynaud, Christophe & Eisenstein, Odile (2023). Solid-State 19F NMR Chemical Shift in Square-Planar Nickel-Fluoride Complexes Linked by Halogen Bonds. Inorganic Chemistry. ISSN 0020-1669. 62(12), p. 4835–4846. doi: 10.1021/acs.inorgchem.2c04063. Full text in Research Archive Show summary

  The halogen bond (XB) is a highly directional class of noncovalent interactions widely explored by experimental and computational studies. However, the NMR signature of the XB has attracted limited attention. The prediction and analysis of the solid-state NMR (SSNMR) chemical shift tensor provide useful strategies to better understand XB interactions. In this work, we employ a computational protocol for modeling and analyzing the 19F SSNMR chemical shifts previously measured in a family of square-planar trans NiII-L2-iodoaryl-fluoride (L = PEt3) complexes capable of forming self-complementary networks held by a NiF···I(C) halogen bond [Thangavadivale, V.; Chem. Sci. 2018, 9, 3767−3781]. To understand how the 19F NMR resonances of the nickel-bonded fluoride are affected by the XB, we investigate the origin of the shielding in trans-[NiF(2,3,5,6-C6F4I)(PEt3)2], trans-[NiF(2,3,4,5-C6F4I)(PEt3)2], and trans-[NiF(C6F5)(PEt3)2] in the solid state, where a XB is present in the two former systems but not in the last. We perform the 19F NMR chemical shift calculations both in periodic and molecular models. The results show that the crystal packing has little influence on the NMR signatures of the XB, and the NMR can be modeled successfully with a pair of molecules interacting via the XB. Thus, the observed difference in chemical shift between solid-state and solution NMR can be essentially attributed to the XB interaction. The very high shielding of the fluoride and its driving contributor, the most shielded component of the chemical shift tensor, are well reproduced at the 2c-ZORA level. Analysis of the factors controlling the shielding shows how the highest occupied Ni/F orbitals shield the fluoride in the directions perpendicular to the Ni–F bond and specifically perpendicular to the coordination plane. This shielding arises from the magnetic coupling of the Ni(3d)/F(2p lone pair) orbitals with the vacant σNi–F* orbital, thereby rationalizing the very highly upfield (shielded) resonance of the component (δ33) along this direction. We show that these features are characteristic of square-planar nickel–fluoride complexes. The deshielding of the fluoride in the halogen-bonded systems is attributed to an increase in the energy gap between the occupied and vacant orbitals that are mostly responsible for the paramagnetic terms, notably along the most shielded direction.

• Ledum, Morten; Carrer, Manuel; Sen, Samiran; Li, Xinmeng; Cascella, Michele & Bore, Sigbjørn Løland (2023). HylleraasMD: Massively parallel hybrid particle-field molecular dynamics in Python. Journal of Open Source Software (JOSS). 8(84). doi: 10.21105/joss.04149. Full text in Research Archive Show summary

  Molecular dynamics (MD) is a computational methodology in which the dynamical behavior of systems of interacting atoms and molecules is investigated by integrating the corresponding classical equations of motion. The analysis of the molecular trajectories yields an incredibly powerful computational microscope with atomic resolution. While prominent examples of molecular dynamics involving all-atom models exist, many systems operate on time- and lengths scales too large, precluding the use of such an approach. The intrinsic complexity of biological soft-matter systems has necessitated the development of coarse-grained (CG) MD models wherein groups of atoms are treated as individual entities. To probe experimentally relevant length- (nm–μm) and time- (ps–ms) scales, further reduction of computational complexity may be warranted through the removal of explicit particle–particle interactions in favor of particle–density field interactions. Such hybrid particle–field (hPF) models recast the interactions between particle pairs into a system of free particles interacting with an external potential dependent on the density, in analogy with self-consistent field theories. HylleraasMD (named after our affiliate centre, the Hylleraas Centre for Quantum Molecular Sciences) (HyMD) is a Python package capable of highly parallel hPF-MD simulations of a wide range of surfactants and other biological systems in a CG representation. At present, it is the only open-source implementation of the hPF formalism freely available to computational researchers.

• Thorbjørnsrud, Helen Vikdal; Bressan, Lucas; Khatanbaatar, Tamjidmaa; Carrer, Manuel; Würth-Roderer, Kathrin & Cordara, Gabriele [Show all 9 contributors for this article] (2023). What Drives Chorismate Mutase to Top Performance? Insights from a Combined In Silico and In Vitro Study. Biochemistry. ISSN 0006-2960. 62(3), p. 782–796. doi: 10.1021/acs.biochem.2c00635. Full text in Research Archive Show summary

  Unlike typical chorismate mutases, the enzyme from Mycobacterium tuberculosis (MtCM) has only low activity on its own. Remarkably, its catalytic efficiency kcat/Km can be boosted more than 100-fold by complex formation with a partner enzyme. Recently, an autonomously fully active MtCM variant was generated using directed evolution, and its structure was solved by X-ray crystallography. However, key residues were involved in crystal contacts, challenging the functional interpretation of the structural changes. Here, we address these challenges by microsecond molecular dynamics simulations, followed up by additional kinetic and structural analyses of selected sets of specifically engineered enzyme variants. A comparison of wild-type MtCM with naturally and artificially activated MtCMs revealed the overall dynamic profiles of these enzymes as well as key interactions between the C-terminus and the active site loop. In the artificially evolved variant of this model enzyme, this loop is preorganized and stabilized by Pro52 and Asp55, two highly conserved residues in typical, highly active chorismate mutases. Asp55 stretches across the active site and helps to appropriately position active site residues Arg18 and Arg46 for catalysis. The role of Asp55 can be taken over by another acidic residue, if introduced at position 88 close to the C-terminus of MtCM, as suggested by molecular dynamics simulations and confirmed by kinetic investigations of engineered variants.

• Ledum, Morten; Sen, Samiran; Bore, Sigbjørn Løland & Cascella, Michele (2023). On the equivalence of the hybrid particle-field and Gaussian core models. Journal of Chemical Physics. ISSN 0021-9606. 158(19). doi: 10.1063/5.0145142. Full text in Research Archive Show summary

  Hybrid particle–field molecular dynamics is a molecular simulation strategy, wherein particles couple to a density field instead of through ordinary pair potentials. Traditionally considered a mean-field theory, a momentum and energy-conserving hybrid particle–field formalism has recently been introduced, which was demonstrated to approach the Gaussian Core model potential in the grid-converged limit. Here, we expand on and generalize the correspondence between the Hamiltonian hybrid particle–field method and particle–particle pair potentials. Using the spectral procedure suggested by Bore and Cascella, we establish compatibility to any local soft pair potential in the limit of infinitesimal grid spacing. Furthermore, we document how the mean-field regime often observed in hybrid particle–field simulations is due to the systems under consideration, and not an inherent property of the model. Considering the Gaussian filter form, in particular, we demonstrate the ability of the Hamiltonian hybrid particle–field model to recover all structural and dynamical properties of the Gaussian Core model, including solid phases, a first-order phase transition, and anomalous transport properties. We quantify the impact of the grid spacing on the correspondence, as well as the effect of the particle–field filtering length scale on the emergent particle–particle correlations.

• Cascella, Michele & Silva, Thereza Amelia Soares da (2022). Bias Amplification in Gender, Gender Identity, and Geographical Affiliation. Journal of Geophysical Research (JGR): Solid Earth. ISSN 2169-9313. doi: 10.1021/acs.jcim.2c00533. Full text in Research Archive Show summary

  In the quest for greater equity in science, individual attitudes and institutional policies should also embrace greater diversity and inclusion of minority groups. This viewpoint calls for a broader definition of gender bias in STEM to include gender identity and for increased attention to the issue of bias amplification due to geographic affiliation in the field of computational chemistry and chemoinformatics. It briefly discusses some active interventions to tackle bias on gender, gender identity, and geographic affiliation in STEM.

• Sekulic, Nikolina; Hovet, Oda; Gogoi, Hemanga; Dawicki-McKenna, Jennine; Wøien, Stine Malene Hansen & Carrer, Manuel [Show all 8 contributors for this article] (2022). The structural basis of the multi-step allosteric activation of Aurora B kinase. BioRxiv. ISSN 0362-4331. Full text in Research Archive
• Thorbjørnsrud, Helen Vikdal; Bressan, Luca; Khatanbaatar, Tamjidmaa; Carrer, Manuel; Würth-Roderer, Kathrin & Cordara, Gabriele [Show all 9 contributors for this article] (2022). What drives chorismate mutase to top performance? Insights from a combined in silico and in vitro study. BioRxiv. ISSN 0362-4331. doi: 10.1101/2022.11.08.515563. Full text in Research Archive
• Aeschimann, Walter; Kammer, Stephan; Staats, Stefanie; Schneider, Petra; Schneider, Gisbert & Rimbach, Gerald [Show all 8 contributors for this article] (2021). Engineering of a functional γ-tocopherol transfer protein. Redox Biology. 38. doi: 10.1016/j.redox.2020.101773. Full text in Research Archive Show summary

  α-tocopherol transfer protein (TTP) was previously reported to self-aggregate into 24-meric spheres (α-TTPS) and to possess transcytotic potency across mono-layers of human umbilical vein endothelial cells (HUVECs). In this work, we describe the characterisation of a functional TTP variant with its vitamer selectivity shifted towards γ-tocopherol. The shift was obtained by introducing an alanine to leucine substitution into the substrate-binding pocket at position 156 through site directed mutagenesis. We report here the X-ray crystal structure of the γ-tocopherol specific particle (γ-TTPS) at 2.24 Å resolution. γ-TTPS features full functionality compared to its α-tocopherol specific parent including self-aggregation potency and transcytotic activity in trans-well experiments using primary HUVEC cells. The impact of the A156L mutation on TTP function is quantified in vitro by measuring the affinity towards γ-tocopherol through micro-differential scanning calorimetry and by determining its ligand-transfer activity. Finally, cell culture experiments using adherently grown HUVEC cells indicate that the protomers of γ-TTP, in contrast to α-TTP, do not counteract cytokine-mediated inflammation at a transcriptional level. Our results suggest that the A156L substitution in TTP is fully functional and has the potential to pave the way for further experiments towards the understanding of α-tocopherol homeostasis in humans.

• Kirsch, Till; Olsen, Jógvan Magnus Haugaard; Bolnykh, Viacheslav; Meloni, Simone; Ippoliti, Emiliano & Rothlisberger, Ursula [Show all 8 contributors for this article] (2021). Wavefunction-Based Electrostatic-Embedding QM/MM Using CFOUR through MiMiC. Journal of Chemical Theory and Computation. ISSN 1549-9618. doi: 10.1021/acs.jctc.1c00878. Full text in Research Archive Show summary

  We present an interface of the wavefunction-based quantum chemical software CFOUR to the multiscale modeling framework MiMiC. Electrostatic embedding of the quantum mechanical (QM) part is achieved by analytic evaluation of one-electron integrals in CFOUR, while the rest of the QM/molecular mechanical (MM) operations are treated according to the previous MiMiC-based QM/MM implementation. Long-range electrostatic interactions are treated by a multipole expansion of the potential from the QM electron density to reduce the computational cost without loss of accuracy. Testing on model water/water systems, we verified that the CFOUR interface to MiMiC is robust, guaranteeing fast convergence of the self-consistent field cycles and optimal conservation of the energy during the integration of the equations of motion. Finally, we verified that the CFOUR interface to MiMiC is compatible with the use of a QM/QM multiple time-step algorithm, which effectively reduces the cost of ab initio MD (AIMD) or QM/MM-MD simulations using higher level wavefunction-based approaches compared to cheaper density functional theory-based ones. The new wavefunction-based AIMD and QM/MM-MD implementations were tested and validated for a large number of wavefunction approaches, including Hartree–Fock and post-Hartree–Fock methods like Møller–Plesset, coupled-cluster, and complete active space self-consistent field.

• Ledum, Morten; Bore, Sigbjørn Løland & Cascella, Michele (2020). Automated determination of hybrid particle-field parameters by machine learning. Molecular Physics. ISSN 0026-8976. 118(19-20), p. 1–12. doi: 10.1080/00268976.2020.1785571. Full text in Research Archive Show summary

  The hybrid particle-field molecular dynamics method is an efficient alternative to standard particle-based coarse grained approaches. In this work, we propose an automated protocol for optimisation of the effective parameters that define the interaction energy density functional, based on Bayesian optimisation. The machine-learning protocol makes use of an arbitrary fitness function defined upon a set of observables of relevance, which are optimally matched by an iterative process. Employing phospholipid bilayers as test systems, we demonstrate that the parameters obtained through our protocol are able to reproduce reference data better than currently employed sets derived by Flory-Huggins models. The optimisation procedure is robust and yields physically sound values. Moreover, we show that the parameters are satisfactorily transferable among chemically analogous species. Our protocol is general, and does not require heuristic a posteriori rebalancing. Therefore it is particularly suited for optimisation of reliable hybrid particle-field potentials of complex chemical mixtures, and extends the applicability corresponding simulations to all those systems for which calibration of the density functionals may not be done via simple theoretical models.

• Schäfer, Ken; Kolli, Hima Bindu; Christensen, Mikkel Killingmoe; Bore, Sigbjørn Løland; Diezemann, Gregor & Gauss, Jürgen [Show all 9 contributors for this article] (2020). Supramolecular Packing Drives Morphological Transitions of Charged Surfactant Micelles. Angewandte Chemie International Edition. ISSN 1433-7851. 59(42), p. 18591–18598. doi: 10.1002/anie.202004522. Full text in Research Archive Show summary

  The shape and size of self‐assembled structures upon local organization of their molecular building blocks are hard to predict in the presence of long‐range interactions. Combining small‐angle X‐ray/neutron scattering data, theoretical modelling, and computer simulations, sodium dodecyl sulfate (SDS), over a broad range of concentrations and ionic strengths, was investigated. Computer simulations indicate that micellar shape changes are associated with different binding of the counterions. By employing a toy model based on point charges on a surface, and comparing it to experiments and simulations, it is demonstrated that the observed morphological changes are caused by symmetry breaking of the irreducible building blocks, with the formation of transient surfactant dimers mediated by the counterions that promote the stabilization of cylindrical instead of spherical micelles. The present model is of general applicability and can be extended to all systems controlled by the presence of mobile charges.

• Bore, Sigbjørn Løland & Cascella, Michele (2020). Hamiltonian and alias-free hybrid particle-field molecular dynamics. Journal of Chemical Physics. ISSN 0021-9606. 153(9). doi: 10.1063/5.0020733. Full text in Research Archive Show summary

  Hybrid particle–field molecular dynamics combines standard molecular potentials with density-field models into a computationally efficient methodology that is well-adapted for the study of mesoscale soft matter systems. Here, we introduce a new formulation based on filtered densities and a particle–mesh formalism that allows for Hamiltonian dynamics and alias-free force computation. This is achieved by introducing a length scale for the particle–field interactions independent of the numerical grid used to represent the density fields, enabling systematic convergence of the forces upon grid refinement. Our scheme generalizes the original particle–field molecular dynamics implementations presented in the literature, finding them as limit conditions. The accuracy of this new formulation is benchmarked by considering simple monoatomic systems described by the standard hybrid particle–field potentials. We find that by controlling the time step and grid size, conservation of energy and momenta, as well as disappearance of alias, is obtained. Increasing the particle–field interaction length scale permits the use of larger time steps and coarser grids. This promotes the use of multiple time step strategies over the quasi-instantaneous approximation, which is found to not conserve energy and momenta equally well. Finally, our investigations of the structural and dynamic properties of simple monoatomic systems show a consistent behavior between the present formulation and Gaussian core models.

• Carrer, Manuel; Skrbic, Tatjana; Bore, Sigbjørn Løland; Milano, Giuseppe; Cascella, Michele & Giacometti, Achille (2020). Can Polarity-Inverted Surfactants Self-Assemble in Nonpolar Solvents? Journal of Physical Chemistry B. ISSN 1520-6106. 124, p. 6448–6458. doi: 10.1021/acs.jpcb.0c04842. Full text in Research Archive Show summary

  We investigate the self-assembly process of a surfactant with inverted polarity in water and cyclohexane using both all-atom and coarse-grained hybrid particle-field molecular dynamics simulations. Unlike conventional surfactants, the molecule under study, proposed in a recent experiment, is formed by a rigid and compact hydrophobic adamantane moiety, and a long and floppy triethylene glycol tail. In water, we report the formation of stable inverted micelles with the adamantane heads grouping together into a hydrophobic core and the tails forming hydrogen bonds with water. By contrast, microsecond simulations do not provide evidence of stable micelle formation in cyclohexane. Validating the computational results by comparison with experimental diffusion constant and small-angle X-ray scattering intensity, we show that at laboratory thermodynamic conditions the mixture resides in the supercritical region of the phase diagram, where aggregated and free surfactant states coexist in solution. Our simulations also provide indications as to how to escape this region to produce thermodynamically stable micellar aggregates.

• Castro, Abril C; Balcells, David; Repisky, Michal; Helgaker, Trygve & Cascella, Michele (2020). First-principles calculation of 1H NMR chemical shifts of complex metal polyhydrides: The essential inclusion of relativity and dynamics. Inorganic Chemistry. ISSN 0020-1669. 59(23), p. 17509–17518. doi: 10.1021/acs.inorgchem.0c02753. Full text in Research Archive Show summary

  ¹H NMR spectroscopy has become an important technique for the characterization of transition-metal hydride complexes, whose metal-bound hydrides are often difficult to locate by X-ray diffraction. In this regard, the accurate prediction of ¹H NMR chemical shifts provides a useful, but challenging, strategy to help in the interpretation of the experimental spectra. In this work, we establish a density-functional-theory protocol that includes relativistic, solvent, and dynamic effects at a high level of theory, allowing us to report an accurate and reliable interpretation of ¹H NMR hydride chemical shifts of iridium polyhydride complexes. In particular, we have studied in detail the hydride chemical shifts of the [Ir₆(IMe)₈(CO)₂H₁₄]²⁺ complex in order to validate previous assignments. The computed ¹H NMR chemical shifts are strongly dependent on the relativistic treatment, the choice of the DFT exchange–correlation functional, and the conformational dynamics. By combining a fully relativistic four-component electronic-structure treatment with ab initio molecular dynamics, we were able to reliably model both the terminal and bridging hydride chemical shifts and to show that two NMR hydride signals were inversely assigned in the experiment.

• Peltzer, Raphael Mathias; Gauss, Jürgen; Eisenstein, Odile & Cascella, Michele (2020). The Grignard Reaction − Unraveling a Chemical Puzzle. Journal of the American Chemical Society. ISSN 0002-7863. 142(6), p. 2984–2994. doi: 10.1021/jacs.9b11829. Full text in Research Archive Show summary

  More than 100 years since its discovery, the mechanism of the Grignard reaction remains unresolved. Ambiguities arise from the concomitant presence of multiple organomagnesium species and the competing mechanisms involving either nucleophilic addition or the formation of radical intermediates. To shed light on this topic, quantum-chemical calculations and ab initio molecular dynamics simulations are used to study the reaction of CH3MgCl in tetrahydrofuran with acetaldehyde and fluorenone as prototypical reagents. All organomagnesium species coexisting in solution due to the Schlenk equilibrium are found to be competent reagents for the nucleophilic pathway. The range of activation energies displayed by all of these compounds is relatively small. The most reactive species are a dinuclear Mg complex in which the substrate and the nucleophile initially bind to different Mg centers and the mononuclear dimethyl magnesium. The radical reaction, which requires the homolytic cleavage of the Mg–CH3 bond, cannot occur unless a substrate with a low-lying π*(CO) orbital coordinates the Mg center. This rationalizes why a radical mechanism is detected only in the presence of substrates with a low reduction potential. This feature, in turn, does not necessarily favor the nucleophilic addition, as shown for the reaction with fluorenone. The solvent needs to be considered as a reactant for both the nucleophilic and the radical reactions, and its dynamics is essential for representing the energy profile. The similar reactivity of several species in fast equilibrium implies that the reaction does not occur via a single process but by an ensemble of parallel reactions.

• Nicola, Antonio De; Soares, Thereza; Santos, Denys ES; Bore, Sigbjørn Løland; Sevink, G J Agur & Cascella, Michele [Show all 7 contributors for this article] (2020). Aggregation of Lipid A Variants: A Hybrid Particle-Field Model. Biochimica et Biophysica Acta - General Subjects. ISSN 0304-4165. 1865. doi: 10.1016/j.bbagen.2020.129570. Full text in Research Archive Show summary

  Lipid A is one of the three components of bacterial lipopolysaccharides constituting the outer membrane of Gram-negative bacteria, and is recognized to have an important biological role in the inflammatory response of mammalians. Its biological activity is modulated by the number of acyl-chains that are present in the lipid and by the dielectric medium, i.e., the type of counter-ions, through electrostatic interactions. In this paper, we report on a coarse-grained model of chemical variants of Lipid A based on the hybrid particle-field/molecular dynamics approach (hPF-MD). In particular, we investigate the stability of Lipid A bilayers for two different hexa- and tetra-acylated structures. Comparing particle density profiles along bilayer cross-sections, we find good agreement between the hPF-MD model and reference all-atom simulation for both chemical variants of Lipid A. hPF-MD models of constituted bilayers composed by hexa-acylated Lipid A in water are stable within the simulation time. We further validate our model by verifying that the phase behavior of Lipid A/counterion/water mixtures is correctly reproduced. In particular, hPF-MD simulations predict the correct self-assembly of different lamellar and micellar phases from an initially random distribution of Lipid A molecules with counterions in water. Finally, it is possible to observe the spontaneous formation and stability of Lipid A vesicles by fusion of micellar aggregates.

• Bore, Sigbjørn Løland; Kolli, Hima Bindu; Nicola, Antonio De; Byshkin, Maksym; Kawakatsu, Toshihiro & Milano, Giuseppe [Show all 7 contributors for this article] (2020). Hybrid Particle-Field Molecular Dynamics Under Constant Pressure. Journal of Chemical Physics. ISSN 0021-9606. 152(18). doi: 10.1063/5.0007445. Full text in Research Archive Show summary

  Hybrid particle-field methods are computationally efficient approaches for modeling soft matter systems. So far, applications of these methodologies have been limited to constant volume conditions. Here, we reformulate particle-field interactions to represent systems coupled to constant external pressure. First, we show that the commonly used particle-field energy functional can be modified to model and parameterize the isotropic contributions to the pressure tensor without interfering with the microscopic forces on the particles. Second, we employ a square gradient particle-field interaction term to model non-isotropic contributions to the pressure tensor, such as in surface tension phenomena. This formulation is implemented within the hybrid particle-field molecular dynamics approach and is tested on a series of model systems. Simulations of a homogeneous water box demonstrate that it is possible to parameterize the equation of state to reproduce any target density for a given external pressure. Moreover, the same parameterization is transferable to systems of similar coarse-grained mapping resolution. Finally, we evaluate the feasibility of the proposed approach on coarse-grained models of phospholipids, finding that the term between water and the lipid hydrocarbon tails is alone sufficient to reproduce the experimental area per lipid in constant-pressure simulations and to produce a qualitatively correct lateral pressure profile.

• Franco-Ulloa, Sebastian; Tatulli, Giuseppina; Bore, Sigbjørn Løland; Moglianetti, Mauro; Pompa, Pier Paolo & Cascella, Michele [Show all 7 contributors for this article] (2020). Dispersion state phase diagram of citrate-coated metallic nanoparticles in saline solutions. Nature Communications. 11. doi: 10.1038/s41467-020-19164-3. Full text in Research Archive Show summary

  Abstract The fundamental interactions underlying citrate-mediated chemical stability of metal nanoparticles, and their surface characteristics dictating particle dispersion/aggregation in aqueous solutions, are largely unclear. Here, we developed a theoretical model to estimate the stoichiometry of small, charged ligands (like citrate) chemisorbed onto spherical metallic nanoparticles and coupled it with atomistic molecular dynamics simulations to define the uncovered solvent-accessible surface area of the nanoparticle. Then, we integrated coarse-grained molecular dynamics simulations and two-body free energy calculations to define dispersion state phase diagrams for charged metal nanoparticles in a range of medium’s ionic strength, a known trigger for aggregation. Ultraviolet-visible spectroscopy experiments of citrate-capped nanocolloids validated our predictions and extended our results to nanoparticles up to 35 nm. Altogether, our results disclose a complex interplay between the particle size, its surface charge density, and the ionic strength of the medium, which ultimately clarifies how these variables impact colloidal stability.

• Castro, Abril C.; Fliegl, Heike; Cascella, Michele; Helgaker, Trygve; Repisky, Michal & Komorovsky, Stanislav [Show all 9 contributors for this article] (2019). Four-component relativistic 31P NMR calculations for: Trans -platinum(ii) complexes: Importance of the solvent and dynamics in spectral simulations. Dalton Transactions. ISSN 1477-9226. 48(23), p. 8076–8083. doi: 10.1039/c9dt00570f. Full text in Research Archive Show summary

  We report a combined experimental-theoretical study on the 31P NMR chemical shift for a number of trans-platinum(II) complexes. Validity and reliability of the 31P NMR chemical shift calculations are examined by comparing with the experimental data. A successful computational protocol for the accurate prediction of the 31P NMR chemical shifts was established for trans-[PtCl2(dma)PPh3] (dma = dimethylamine) complex. The reliability of the computed values is shown to be critically dependent on the level of relativistic effects (two-component vs. four component), choice of density functional, dynamical averaging, and solvation effects. Snapshots from ab initio molecular dynamics simulations were used to identify those solvent molecules which show the largest interactions with the platinum complex, through inspection by the non-covalent interaction program. We observe satisfactory accuracy from the full four-component matrix Dirac-Kohn-Sham method (mDKS) based on the Dirac-Coulomb Hamiltonian, in conjunction with the KT2 density functional, and dynamical averaging with explicit solvent molecules

• Bore, Sigbjørn Løland; Kolli, Hima Bindu; Kawakatsu, Toshihiro; Milano, Giuseppe & Cascella, Michele (2019). Mesoscale Electrostatics Driving Particle Dynamics in Nonhomogeneous Dielectrics. Journal of Chemical Theory and Computation. ISSN 1549-9618. 15(3), p. 2033–2041. doi: 10.1021/acs.jctc.8b01201. Full text in Research Archive
• Kolli, Hima Bindu; Nicola, Antonio De; Bore, Sigbjørn Løland; Schäfer, Ken; Diezemann, Gregor & Gauss, Jürgen [Show all 11 contributors for this article] (2018). Hybrid particle-field molecular dynamics simulations of charged amphiphiles in an aqueous environment. Journal of Chemical Theory and Computation. ISSN 1549-9618. 14(9), p. 4928–4937. doi: 10.1021/acs.jctc.8b00466. Full text in Research Archive Show summary

  We develop and test specific coarse-grained models for charged amphiphilic systems such as palmitoyloleoylphosphatidylglycerol (POPG) lipid bilayer and sodium dodecyl sulfate (SDS) surfactant in an aqueous environment, to verify the ability of the hybrid particle-field method to provide a realistic description of polyelectrolytes. According to the hybrid approach, the intramolecular interactions are treated by a standard molecular Hamiltonian, and the nonelectrostatic intermolecular forces are described by density fields. Electrostatics is introduced as an additional external field obtained by a modified particle-mesh Ewald procedure, as recently proposed [Zhu et al. Phys. Chem. Chem. Phys. 2016, 18, 9799]. Our results show that, upon proper calibration of key parameters, electrostatic forces can be correctly reproduced. Molecular dynamics simulations indicate that the methodology is robust with respect to the choice of the relative dielectric constant, yielding the same correct qualitative behavior for a broad range of values. In particular, our methodology reproduces well the organization of the POPG bilayer, as well as the SDS concentration-dependent change in the morphology of the micelles from spherical to microtubular aggregates. The inclusion of explicit electrostatics with good accuracy and low computational cost paves the way for a significant extension of the hybrid particle-field method to biological systems, where the polyelectrolyte component plays a fundamental role for both structural and dynamical molecular properties. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review and technical editing by the publisher.

• Sommer, Theis; Bjerregaard-Andersen, Kaare; Uribe, Lalita; Etzerodt, Michael; Diezemann, Gregor & Gauss, Jürgen [Show all 8 contributors for this article] (2018). A fundamental catalytic difference between zinc and manganese dependent enzymes revealed in a bacterial isatin hydrolase. Scientific Reports. 8(13104), p. 1–11. doi: 10.1038/s41598-018-31259-y. Full text in Research Archive Show summary

  The catalytic mechanism of the cyclic amidohydrolase isatin hydrolase depends on a catalytically active manganese in the substrate-binding pocket. The Mn2+ ion is bound by a motif also present in other metal dependent hydrolases like the bacterial kynurenine formamidase. The crystal structures of the isatin hydrolases from Labrenzia aggregata and Ralstonia solanacearum combined with activity assays allow for the identification of key determinants specific for the reaction mechanism. Active site residues central to the hydrolytic mechanism include a novel catalytic triad Asp-His-His supported by structural comparison and hybrid quantum mechanics/classical mechanics simulations. A hydrolytic mechanism for a Mn2+ dependent amidohydrolases that disfavour Zn2+ as the primary catalytically active site metal proposed here is supported by these likely cases of convergent evolution. The work illustrates a fundamental difference in the substrate-binding mode between Mn2+ dependent isatin hydrolase like enzymes in comparison with the vast number of Zn2+ dependent enzymes.

• Jaschonek, Stefan; Cascella, Michele; Gauss, Jurgen; Diezemann, Gregor & Milano, Giuseppe (2018). Intramolecular structural parameters are key modulators of the gel-liquid transition in coarse grained simulations of DPPC and DOPC lipid bilayers. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 498(2), p. 327–333. doi: 10.1016/j.bbrc.2017.10.132. Full text in Research Archive Show summary

  The capability of coarse-grained models based on the MARTINI mapping to reproduce the gel-liquid phase transition in saturated and unsaturated model lipids was investigated. We found that the model is able to reproduce a lower critical temperature for 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) with respect to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Nonetheless, the appearance of a gel phase for DOPC is strictly dependent on the intramolecular parameters chosen to model its molecular structure. In particular, we show that the bending angle at the coarse-grained bead corresponding to the unsaturated carbon-carbon bond acts as an order parameter determining the temperature of the phase transition. Structural analysis of the molecular dynamics simulations runs evidences that in the gel phase, the packing of the lipophilic tails of DOPC assume a different conformation than in the liquid phase. In the latter phase, the DOPC geometry resembles that of the relaxed free molecule. DPPC:DOPC mixtures show a single phase transition temperature, indicating that the observation of a phase separation between the two lipids requires the simulation of systems with sizes much larger than the ones used here.

• Bore, Sigbjørn Løland; Milano, Giuseppe & Cascella, Michele (2018). Hybrid Particle-Field Model for Conformational Dynamics of Peptide Chains. Journal of Chemical Theory and Computation. ISSN 1549-9618. 14(2), p. 1120–1130. doi: 10.1021/acs.jctc.7b01160. Full text in Research Archive Show summary

  We propose the first model of a polypeptide chain based on a hybrid-particle field approach. The intramolecular potential is built on a two-bead coarse grain mapping for each amino acid. We employ a combined potential for the bending and the torsional degrees of freedom that ensures the stabilization of secondary structure elements in the conformational space of the polypeptide. The electrostatic dipoles associated with the peptide bonds of the main chain are reconstructed by a topological procedure. The intermolecular interactions comprising both the solute and the explicit solvent are treated by a density functional-based mean-field potential. Molecular dynamics simulations on a series of test systems show how the model here introduced is able to capture all the main features of polypeptides. In particular, homopolymers of different lengths yield a complex folding phase diagram, covering from the collapsed to swollen state. Moreover, simulations on models of a four-helix bundle and of an alpha + beta peptide evidence how the collapse of the hydrophobic core drives the appearance of both folded motifs and the stabilization of tertiary or quaternary assemblies. Finally, the polypeptide model is able to structurally respond to the environmental changes caused by the presence of a lipid bilayer. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review and technical editing by the publisher.

• Correa, Andrea; Cascella, Michele; Scotti, Nicola; Zaccheria, Federica; Ravasio, Nicoletta & Psaro, Rinaldo (2018). Mechanistic insights into formic acid dehydrogenation promoted by Cu-amino based systems. Inorganica Chimica Acta. ISSN 0020-1693. 470, p. 290–294. doi: 10.1016/j.ica.2017.06.043. Full text in Research Archive Show summary

  A computational study on the molecular mechanism of formic acid dehydrogenation in the presence of Cu-amine complex has been carried out in order to shed light on the role of the amine in determining the catalyst activity. The migration of H from the formate ligand to the metal center has been investigated in detail due to its endothermic nature. The relevance of both basicity and steric hindrance of the amine, as well as its binding ability to the metal center, in promoting hydrogen evolution has been confirmed.

• Peltzer, Raphael Mathias; Kolli, Hima Bindu; Stocker, Achim & Cascella, Michele (2018). Self-assembly of alpha-tocopherol transfer protein nanoparticles: a patchy-protein model. Journal of Physical Chemistry B. ISSN 1520-6106. 122(28), p. 7066–7072. doi: 10.1021/acs.jpcb.8b05936. Full text in Research Archive Show summary

  We describe the mechanism of self-aggregation of α-tocopherol transfer protein into a spherical nanocage employing Monte Carlo simulations. The protein is modeled by a patchy coarse-grained representation, where the protein–protein interfaces, determined in the past by X-ray diffraction, are represented by simplified two-body interaction potentials. Our results show that the oligomerization kinetics proceeds in two steps, with the formation of metastable trimeric units and the subsequent assembly into the spherical aggregates. Data are in agreement with experimental observations regarding the prevalence of different aggregation states at specific ambient conditions. Finally, our results indicate a route for the experimental stabilization of the trimer, crucial for the understanding of the physiological role of such aggregates in vitamin E body trafficking.

• Uribe, Lalita; Diezemann, Gregor; Gauss, Jürgen; Morth, Jens Preben & Cascella, Michele (2018). Structural origin of metal specificity in isatin hydrolase from Labrenzia aggregata investigated by computer simulations. Chemistry - A European Journal. ISSN 0947-6539. 24(20), p. 5074–5077. doi: 10.1002/chem.201705159. Full text in Research Archive

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• Cascella, Michele & Potestio, Raffaello (2025). Theoretical foundations of multiscale modelling. Elsevier. ISBN 9780323884402. 360 p. doi: 10.1016/C2020-0-03594-2. Full text in Research Archive
• Eisenstein, Odile; Cascella, Michele & Pradier, Claire-Marie (2021). La reaction de Grignard, une enigme de 120 ans chapter in Etonnante Chimie Decouvertes et promesses du XXIeme siècle. CNRS Editions. ISBN 9782271136527. 340 p. Full text in Research Archive

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• Cascella, Michele (2026). A Multi-scale view on Grignard Chemistry. Full text in Research Archive
• Cortés, Natalia Mojica; Kersten, Flore; Serrano, Albert; Heim, Joel Benjamin; Cordara, Gabriele & Teter, Ken [Show all 8 contributors for this article] (2026). Why is cholera toxin more toxic than heat-labile enterotoxin? Insights from protein crystallography and MD simulations. Full text in Research Archive
• Cascella, Michele (2025). Mechanisms of self-assembling of non-conventional surfactants by multi-scale modelling and data-driven approaches. Full text in Research Archive
• Pedersen, Thomas Bondo; Tellgren, Erik; Cascella, Michele & Coriani, Sonia (2025). Tribute to Trygve Helgaker. Journal of Physical Chemistry A. ISSN 1089-5639. 129(50), p. 11469–11470. doi: 10.1021/acs.jpca.5c07794. Full text in Research Archive
• Cezar, Henrique Musseli; Bjørnestad, Victoria Ariel; Lund, Reidar & Cascella, Michele (2024). Metainference simulations to interpret small-angle scattering experiments of non-conventional surfactants. Full text in Research Archive
• Cezar, Henrique Musseli; Bjørnestad, Victoria Ariel; Lund, Reidar & Cascella, Michele (2024). Metainference simulations to interpret small angle scattering experiments of non-conventional surfactants. Full text in Research Archive
• Eliasson, Sondre Hilmar Hopen; Giovanetti, Marinella de; Bore, Sigbjørn Løland; Cascella, Michele & Eisenstein, Odile (2024). Machine Learned Potential for Organolithium Compounds in THF. Full text in Research Archive
• Eliasson, Sondre Hilmar Hopen; Giovanetti, Marinella de; Bore, Sigbjørn Løland; Cascella, Michele & Eisenstein, Odile (2024). Machine Learned Potential for Organolithium Compounds in THF. Full text in Research Archive
• Cezar, Henrique Musseli; Bjørnestad, Victoria Ariel; Lund, Reidar & Cascella, Michele (2024). Metainference simulations to interpret small angle scattering experiments. Full text in Research Archive
• Cascella, Michele (2024). Grignard Chemistry Revisited: a Multi-scale Perspective. Full text in Research Archive
• Cezar, Henrique Musseli; Bjørnestad, Victoria Ariel; Prévost, Sylvain François; Lund, Reidar & Cascella, Michele (2024). Metainference simulations to interpret small angle scattering experiments. Full text in Research Archive
• Cascella, Michele (2024). The Grignard reaction: using computational chemistry to resolve a cold case. Full text in Research Archive
• Cascella, Michele; Eisenstein, Odile & Herzberg, Nathaniel (2024). Le gang des Grignard démasqué. [Journal]. Le Monde . Full text in Research Archive
• Cascella, Michele (2023). Multiscale approaches for bio/soft matter: investigating self-assembly and dynamics of lipid and surfactants. Full text in Research Archive
• Eliasson, Sondre Hilmar Hopen; Giovanetti, Marinella de; Bore, Sigbjørn Løland; Bortoli, Marco; Cascella, Michele & Eisenstein, Odile (2023). Machine Learned Potential for Organolithium in THF. Full text in Research Archive
• Eliasson, Sondre Hilmar Hopen; Giovanetti, Marinella de; Bore, Sigbjørn Løland; Bortoli, Marco & Cascella, Michele (2023). Machine Learned Potential for Organolithium Compounds in THF. Full text in Research Archive
• Sekulic, Nikolina; Segura-Pena, Dario; Hovet, Oda; Dawicki-McKenna, Jennine; Wøien, Stine Malene Hansen & Black, Ben E. [Show all 7 contributors for this article] (2022). Aurora B activation requires synchronized internal motion initiated by IN-box phosphorylation. Full text in Research Archive
• Segura-Pena, Dario; Hovet, Oda; Dawicki-McKenna, Jennine; Wøien, Stine Malene Hansen; Black, Ben E. & Cascella, Michele [Show all 7 contributors for this article] (2022). The structural basis of the multi-step allosteric activation of Aurora B kinase. Full text in Research Archive
• Segura-Pena, Dario; Hovet, Oda; Dawicki-McKenna, Jennine; Wøien, Stine Malene Hansen; Black, Ben E. & Cascella, Michele [Show all 7 contributors for this article] (2022). HDX and MD as tools to elucidate Aurora B kinase activation mechanism. Full text in Research Archive
• Segura-Pena, Dario; Hovet, Oda; Dawicki-McKenna, Jennine; Wøien, Stine Malene Hansen; Black, Ben E. & Cascella, Michele [Show all 7 contributors for this article] (2022). Phosphorylation structurally organizes the [Aurora B/IN-box] complex and introduces a synchronised internal motion of the enzyme resulting in activation. Full text in Research Archive
• Segura-Pena, Dario; Hovet, Oda; Dawicki-McKenna, Jennine; Wøien, Stine Malene Hansen; Black, Ben E. & Cascella, Michele [Show all 7 contributors for this article] (2022). The structural basis of the multi-step allosteric activation of Aurora B kinase. Full text in Research Archive
• Segura-Pena, Dario; Hovet, Oda; Dawicki-McKenna, Jennine; Wøien, Stine Malene Hansen; Black, Ben E. & Cascella, Michele [Show all 7 contributors for this article] (2022). The structural basis of the multi-step allosteric activation of Aurora B kinase. Full text in Research Archive
• Cascella, Michele (2022). The Grignard reaction - solving a century old problem by molecular simulations. Full text in Research Archive
• Lund, Reidar & Cascella, Michele (2021). Aggregation kinetics and photodynamics of photocontrollable surfactant AzoTMA: a molecular dynamics study. Full text in Research Archive
• Eisenstein, Odile & Cascella, Michele (2021). Grignard reagent and Grignard reaction: Computational approach of a chemical puzzle. Full text in Research Archive
• Cascella, Michele (2020). Recent advances in hybrid particle field: toward biological systems. Full text in Research Archive
• Cascella, Michele (2019). Simulating biological soft systems coupling particles and fields with molecular dynamics. Full text in Research Archive
• Cascella, Michele (2019). Simulating biological systems coupling particles and fields with molecular dynamics. Full text in Research Archive
• Cascella, Michele (2019). Simulating biological systems coupling particles and fields with molecular dynamics. Full text in Research Archive
• Cascella, Michele (2019). Simulating Biological Systems Coupling Particles and Fields with Molecular Dynamics. Full text in Research Archive
• Cascella, Michele (2019). Simulating biological systems coupling particles and fields with molecular dynamics. Full text in Research Archive
• Cascella, Michele (2019). Multiscale simulations of bio/soft-matter using particles and fields. Full text in Research Archive
• Cascella, Michele (2018). Entropy-driven polymorphism in micellar aggregates of a charged surfactant — a multi-scale study. Full text in Research Archive
• Cascella, Michele (2018). Coarse-graining peptides -- From particles to fields. Full text in Research Archive
• Cascella, Michele (2018). Coarse-graining peptides -- from particles to fields. Full text in Research Archive
• Cascella, Michele (2018). Hybrid particle field models for peptide chains. Full text in Research Archive
• Cascella, Michele (2018). Toward Molecular-Resolved Mesoscale Simulations of Soft Matter. Full text in Research Archive
• Cascella, Michele (2018). Hybrid particle-field molecular dynamics: state of the art and challenges. Full text in Research Archive
• Cascella, Michele (2018). Coarse grained models of protein and peptides using particles and fields. Full text in Research Archive
• Cascella, Michele (2017). Coarse-graining peptides -- From particles to fields. Full text in Research Archive
• Carrer, Manuel & Cascella, Michele (2023). From all-atom to mesoscale : bridging the gap with differentiable molecular dynamic. University of Oslo, Faculty of Mathematics and Natural Sciences, Department of Chemistry. Full text in Research Archive
• Sen, Samiran & Cascella, Michele (2023). Advances in Hamiltonian Hybrid Particle–Field Theory: Improving the description of interfacial systems. Universitetet i Oslo. Full text in Research Archive Show summary

  Laws of physics govern the motion of molecules that constitute all materials, living and non-living, in a highly hierarchical organisation, across tremendous scales of size and time. Molecular dynamics provides a direct way of operating these laws to reproduce the natural behaviour of molecular systems at the atomic resolution. Analysis of the resulting molecular trajectories provides us with greater insight into the workings of these complex systems. Soft matter systems such as lipid membranes, proteins and DNA, can vary greatly in their dimensionality from a few nanometres to several millimetres. Computer simulations require a suitable description of their constituting structures and interactions, detailed enough to successfully reproduce their dynamics, yet simple enough for a comprehensive understanding and to costeffectively produce results. High resolution studies call for high computational costs, which, in turn imply limited accessibility to larger systems. This work discusses a methodology to access mesoscale systems with characteristic sizes and time in the order of micrometres and milliseconds, respectively, with molecular resolution. It describes interactions between particles by coupling them to an external density-dependent field potential. The theoretical developments of this study are based on the Hamiltonian formulation of the hybrid particle–field theory (hPF). The seed for its foundation was sowed in 2020, and the current work institutes it by extending its theory into a fully functional molecular dynamics mechanism. In this approach, particle forces are derived from purely mechanical considerations, without resorting to any approximation of statistical mean-field origins. In doing so, rigorous conservation of energy and momentum in grid-converged limits is achieved. Also, by smoothing the densities of the particles, the method is freed from many artefact-causing grid-dependent biases. Alongside constant energy and constant volume simulations, constant pressure simulation techniques are also developed. The current work derives a complete theoretical framework for calculating the internal pressure of a system, and evidences a natural anisotropy in it. Machine learning strategies are employed to optimise the model parameters in order to represent interactions between particles with greater accuracy. In doing so, stress-free conditions are achieved, manifesting in the correct interfacial properties like surface tension, and undulatory motions of lamellar membranes. Achieving a direct description of particle-particle correlations is yet another outcome of the theory. In practice, it means to be able to obtain stable solids and co-existing phases, even in systems with a single-species. Preliminary tests on soft-core Lennard Jones systems indeed show such behaviour. The entire formalism is implemented into the freely available open-source software, HylleraasMD. It uses embarrassingly parallelisable routines written in a combination of Python and Fortran, making it a rather efficient computational approach to achieve equilibrium soft matter systems, for example, self-assembly of lipids both into extended and vesicular structures. Overall, the discussed developments establish a strong foundation in understanding soft mesoscale systems and show several promising avenues to explore in the coming days. It is time to enter into the realm of more realistic and complex biological interfacial systems.

• Mors, Mira & Cascella, Michele (2023). Molecular Modeling of Nucleosome Core Particles. Universitetet i Oslo. Full text in Research Archive Show summary

  Nucleosomes, the basic units of chromatin in eukaryotes, play a critical role in DNA processing such as transcription, replication, and repair. The canonical nucleosome core particle consists of 145 to 147 DNA base pairs wrapped around a histone octamer composed of one (H3-H4)₂ tetramer and two H2A-H2B dimers. This arrangement results in two stacked disks. Although the importance of non-canonical structures with alternative histone conformations in controlling genome organization and regulation has been recognized, our knowledge of them remains limited. In a recent development, unconventional nucleoprotein particles composed of only two types of histones (H3-H4 or CENP-A-H4) have been identified through cryo-electron microscopy. Here, all-atom molecular dynamics simulations are performed on single nucleosome units to elucidate the specific dynamic properties of the octamers forming a di-tetrameric core. The analysis shows that these structures exhibit significant DNA unwrapping compared to the canonical nucleosome. In particular, the histone H3 variant CENP-A, which marks the location of the centromere, shows the most excessive unwrapping of DNA ends from the core, resulting in an almost orthogonal arrangement of the DNA entry/exit sites. The pronounced flexibility for the last ∼ 20 base pairs observed in the simulations is related to the increased interdisk spacing of the DNA superhelical gyres, which is about one and a half times larger than in the corresponding nucleosome core particle with histones H3 or CENP-A. The results consistently indicate that the di-tetrameric stoichiometry of H3-H4 or CENP-A-H4 leads to increased dynamics and to an opening of the core particle, potentially allowing greater access to DNA binding factors.

• Ledum, Morten; Cascella, Michele & Gauss, Jurgen (2022). Hamiltonian hybrid particle–field method for biological soft matter - Efficient simulation and machine learning approaches. Universitetet i Oslo. Full text in Research Archive Show summary

  Hybrid particle–field methods couple coarse-grained particles through a density field-based intermolecular potential. This allows for large-scale and computationally efficient simulations of soft-matter systems while retaining molecular resolution. The recently introduced Hamiltonian hybrid particle–field method now also allows for rigorous energy and momentum conservation in the grid-converged regime, giving hybrid particle–field results a more solid theoretical footing. This dissertation presents the use of the Hamiltonian hybrid particle–field method for biological soft-matter simulations and outlines recent progress made through the development of new algorithmic and methodological approaches. Four research papers are presented, with topics including the implementation of the first open-source and freely accessible hybrid particle–field software, an approach for determining accurate model parameters through machine learning, the introduction of pressure control schemes, and theoretical results on the intrinsic approximations made in the hybrid scheme and their impact on the model dynamics.

• Steinnes, Lasse; Cascella, Michele & Hjorth-Jensen, Morten (2022). Electrostatics in Mesoscale Simulations of Biological Membranes using the Hybrid Particle-Field Approach. Universitetet i Oslo. Full text in Research Archive Show summary

  I develop and apply an iterative method to solve a general Poisson equation in Fourier space, with a variable dielectric. The iterative method is implemented in the molecular dynamics software HylleraasMD, using the Hamiltonian hPF formalism. First, I benchmark the iterative method with known cases. The method reproduces the electrostatic potential from an analytically constructed charge number density. When comparing with the Coulomb interaction of point particles, the iterative method yields reasonable magnitudes in force and energy, and momentum and energy are conserved. In addition, the method reproduces the behaviour of a 5mM electrolytic solution, with ideal monovalent ions dissolved in a biphase of liquid oil and water. Secondly, I simulate systems of Lipid A and Lipid Re with divalent counter-ions in the NVT ensemble, applying two constant dielectric values and two variable dielectric func- tions. Results are benchmarked with density profiles of united-atom simulations of the same systems. Model membranes of Lipid A and Lipid Re are in agreement with the reference membrane, except for low relative dielectric values, implying screening from polar moieties is necessary to preserve a lamellar bilayer. Lastly, I optimize Flory Huggins mixing parameters with Bayesian optimization, for Lipid A. Optimization increase R2-fitness and reduce RMSE-scores, with no significant differ- ences between trajectories for chosen dielectric parameters. Transferred to Lipid Re, optimized parameters give an improvement in R2 and RMSE compared to unoptimized parameters sets, except for the oligosaccharide chain, which is not present in Lipid A.

• Bore, Sigbjørn Løland; Cascella, Michele & Kvaal, Simen (2020). Advances in the Hybrid Particle-Field Approach: Towards Biological Systems. Universitetet i Oslo. Full text in Research Archive Show summary

  This dissertation aims at advancing the capability of hybrid particle-field simulations of representing various physical phenomena relevant to biological systems. While hybrid particle-field simulations are computationally efficient and well adapted for studying mesoscale systems with molecular resolution, this approach has so far predominantly been applied to simple polymers. The computational investigation of systems of higher complexity, such as DNA and proteins, requires development of new models and an extension of the hybrid particle-field methodology. To this end, six research papers are presented. The main research output of these papers consists in both new methods for representing electrostatics and constant-pressure conditions, and new models for proteins and charged lipids within the hybrid particle-field formalism. The work contained in this thesis thus provides key steps towards large-scale realistic representations of biological systems

• Sekulic, Nikolina; Cascella, Michele & Hovet, Oda (2020). Molecular Dynamics Studies on the Essential Mitotic Protein Kinase – Aurora B. Universitetet i Oslo. Full text in Research Archive Show summary

  Aurora B is a serine/threonine protein kinase. Its enzymatic activity is required for accurate chromosome segregation, spindle midzone stability and cell division. Aurora B kinase is always in association with the activator protein, INCENP, and full activity requires auto-phosphorylation of both, a threonine in the activation loop of Aurora B and the serines in the TSS-motif (Threonine-Serine-Serine) present on INCENP. Structural studies have revealed profound conformational changes in the enzyme complex upon auto-phosphorylation and initial hydrogen- deuterium exchange studies indicate structural dynamic changes associated with auto-phosphorylation. In this study, we have used molecular dynamics to simulate three phosphorylation states of the enzyme complex (non-phosphorylated enzyme complex, enzyme complex phosphorylated only in the activation loop of Aurora B and enzyme complex phosphorylated in both loop of Aurora B and INCENP). We found that phosphorylation has a profound impact on the structure and dynamics of Aurora B/INCENP-complex inducing allosteric communication between INCENP and Aurora B. Upon phosphorylation of the threonine in the activation loop of Aurora B, INCENP adopts a dramatic conformational change and comes into close contact with the activation loop region. Other analyzed regions undergoing noticeable structural changes upon phosphorylation are the active site where ATP becomes more stably bound, the activation loop that becomes more rigid and the αG-helix experiencing a shift towards the core of Aurora B. Principle component analysis revealed a synchronized motion in the fully phosphorylated state of the enzyme complex with coupled open-close and activation loop motions, a feature that might contribute to increased activity. The insights into regulation of Aurora B/INCENP-complex provided in our study might help towards generating a more specific inhibitor of Aurora B in future cancer treatment.

• Thorbjørnsrud, Helen Vikdal; Krengel, Ute & Cascella, Michele (2018). Escaping Mediocrity - Activity and Regulation of a Catalytically Inefficient Enzyme. Universistetet i Oslo. Full text in Research Archive
• Peltzer, Raphael Mathias; Cascella, Michele; Pedersen, Thomas Bondo & Helgaker, Trygve (2018). Multi-scale computational modelling of bio-chemical systems in the condensed phase. Universitetet i Oslo. Full text in Research Archive

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