Collaborative Research: Multiscale molecular simulations of protein-mediated bilayer fusion

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INTELLECTUAL MERITPerhaps the most important structure for cellular life as we know it is the lipid bilayer. Lipid molecules, consisting of a water-soluble "head" and water-insoluble "tails", spontaneously assemble into sandwich-like bilayer membranes, which surround all living cells and further compartmentalize the cellular interiors of all eukaryotic organisms the domain of life to which plants, fungi, animals, and humans belong. The network of membranes in a typical eukaryotic cell is very complex and highly dynamic: small compartments bud off from certain membranes like bubbles, carrying cargo from one part of the cell to another, where they can fuse with yet other membranes, including the outer membrane of the cell. Bilayer fusion is therefore a ubiquitous biological process, tightly linked to the transport of material and information, and therefore it is exquisitely controlled by several classes of membrane-associated proteins. These proteins clearly perform work on the fusing membranes, but the intricate sequence of geometric and topological shape transformations they induce on the molecular scale are impossible to observe directly in experiment. In contrast, molecular simulation offers a window onto these details, but until now the relevant length- and time-scales have proven too big to observe even a single fusion event for a realistic system size. This project establishes a collaboration between two investigators with the aim to meet this challenge by combining recent advances in multiscale coarse-grained modeling with enhanced-sampling molecular simulation. Since this strategy allows incorporating important chemical detail while simultaneously representing large-scale membrane deformations, the investigators will be able to elucidate how molecular-level mechanisms drive fusion events across the relevant physiological length- and time-scales. The project proceeds through three phases, namely: (i) modeling the fusion of pristine bilayers with enhanced sampling, (ii) development of coarse-grained models of model fusogenic proteins, the SNARE system, and (iii) combining these two steps into a single methodology. The project will pursue many topics of energetic, morphological, and mechanistic relevance, in particular questions revolving around the so-called hemifusion intermediate state, for which the two outer bilayer leaflets have already fused but a membrane formed by the two inner leaflets still separates the two compartments.BROADER IMPACTSThis project will impact many topics in the biological sciences due to the central importance of bilayer fusion in a variety of biological processes, including intracellular trafficking, viral entry, neurotransmitter release, fertilization, and more. Beyond the specific questions under study, the computational approach envisioned here takes early steps towards efficient simulation of more complicated multiple-protein/multiple-membrane phenomena and will therefore benefit future studies of a wider class of molecular biological topics. To broaden applicability of the research outcomes, the simulation framework developed in this project will be made freely available with tutorials that will support efficient learning and facilitate the transformation of existing techniques and modules towards novel applications. This project establishes cross-disciplinary exchange between engineering and (bio)physics, fostering a stimulating interdisciplinary environment for the academic growth of students mentored in this project. It will further the transfer of theoretical and computational methodologies from engineering and physics into the life sciences and their increasingly quantitative set of problems. The ubiquity of bilayer fusion and its connection to a wide class of fascinating themes in biological physics, which is in itself an intriguing cross-disciplinary subject, also present excellent opportunities for the expertise developed in this project to feed outreach specifically tailored towards groups underrepresented in STEM fields for instance through classroom material, lecture demonstrations, and public talks and both investigators will implement such activities, building on both their experience and existing successful programs at their respective institutions.