Webinar #96: Multiscale simulation of biomembranes: shape, structure and cellular function

BioExcel Webinar
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Biological membranes exhibit intricate, large-scale dynamical architectures that are intimately coupled to cellular function, and abnormal membrane organization is implicated in many diseases. These structures arise from collective molecular interactions. Although these interactions can be described using molecular dynamics simulations, the spatiotemporal scales required to capture membrane organization at cellular and subcellular scale remain beyond the practical reach of such approaches. Meanwhile, rapid advances in experimental techniques now provide unprecedented structural and dynamical detail. Three-dimensional electron microscopy enables visualization of membrane ultrastructure at near-molecular resolution, while super-resolution microscopy reveals membrane dynamics and organization in living cells. These developments create a growing need for computational frameworks capable of bridging molecular detail with mesoscale and cellular-scale phenomena. To address this challenge, I propose integrating mesoscale membrane models into a multiscale simulation framework for biomembranes through systematic mapping and backmapping schemes, enabling the transfer of structural and dynamical information across scales.

In this talk, I will first present a few representative cases demonstrating how large-scale membrane morphology and dynamics regulate molecular-scale processes. I will then introduce a mesoscale simulation framework implemented in the FreeDTS software package and describe its integration into a multiscale modeling pipeline through the TS2CG backmapping scheme. Finally, I will present our recent advances in data-driven mesoscale membrane modeling using the Helfrich Monte Carlo Flexible Fitting (HMFF) approach. This method enables the biasing of membrane simulations using high-resolution structural data from three-dimensional electron microscopy, allowing the generation of statistically meaningful ensembles of membrane morphologies. Together, FreeDTS, HMFF, TS2CG, and conventional molecular dynamics engines constitute a unified multiscale framework that enables simulations of biomembranes across scales.

Any extra questions for @WeriaPezeshkian . please answer to this post

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I would like to thank Weria for the lecture. I have a question:

If you were to inhibit Shiga toxin at the atomistic level with an inhibitor, would this affect the simulation at the mesoscale level? For instance, would the membrane still invaginate in this scenario, and would this be a useful approach to validate inhibitors designed against viral proteins?

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If the inhibition completely blocks Shiga toxin from binding, then the membrane remains flat, as there is nothing to bend it. However, it could be that inhibition leads to weaker binding. That would translate into different model parameters for the proteins, which could result in either tubulation or membrane softening instead of tubulation. The key point is that one should understand what happens at the level of a single Shiga toxin, use that information to obtain model parameters for the mesoscale, and then use the mesoscale model to determine what happens collectively.