Biological systems have developed an impressive array of complex functional structures, such as molecular machines, which drive living processes and hold the key to revolutionizing energy sustainability [1]. Biological functions are the result of a complex interplay through a dynamic network of crowded macromolecules. Intriguingly, large-scale, slow biological events that occur on micrometer and millisecond scales are triggered and regulated by local, fast biochemical events like ligand binding or enzymatic reactions occurring on nanometer and pico/nanosecond scales—for example, as in G protein-coupled receptor signalling cascades.
Multicomponent biological structures arise in multiphase environments—in fact, subcellular processes hardly ever occur at random locations in the cell but are usually compartmented at specific membranes such as the endosome, the endoplasmatic reticulum, or the plasma membrane. To model such complex systems and extract information relevant to experiment, we must draw on the tools of RT1–RT4. In particular, we must go beyond the current description of biological membranes as a periodic lipid bilayer made up of a few chemical components.
We will in RT6 address bacterial antimicrobial resistance, one of the biggest threats to public health [2]. Drug-resistance mechanisms have evolved independently in different bacterial strains and may involve macromolecular complexes such as multidrug efflux pumps. The dimensionality of these transporters is such that only models beyond the state of the art can give a comprehensive description of their mechanisms. Moreover, the peculiar composition of the outer bacterial membranes provides a promising target for the development of specific antibiotics [3], see the figure above. The study of membrane polymorphism under different conditions will involve vastly different time and length scales. Using multiscale methods—in particular, the MD-SCF method of RT2—we will develop protocols for an atomistic description of molecular interactions that trigger biological function (molecular recognition, enzymatic catalysis) and for a mesoscale description of molecular phenomena that generate macro-scopic complex responses. By combining large-scale simulations with the spectroscopic tools developed in RT2 and RT3, we will be able to identify key fingerprints for optically active compounds in different
multiphase environments. Finally, we will use our multiscale tools to investigate biointeractions of nanomaterials, describing, in particular, protein and polymer coating of nanoparticles, important for the development of antifouling, biocompatible materials.
The integration of structural, dynamical and spectroscopic calculations will put us in an excellent position to provide computational protocols to complement data coming from experimental facilities: fourth-generation light sources are heralded as capable of elucidating the statistical laws that govern macromolecular systems through the use of time-resolved soft X-rays; free-electron lasers, cryo-electron microscopy, and novel neutron scattering equipment promise to give new insights into large membrane-associated systems, their dynamics, and structural aggregation.