Research

Plasma membrane is a complex self-assembly of a variety of lipids, sterols and proteins. Differential molecular interactions among these diverse constituents give rise to spatial and dynamic heterogeneities in the membrane structure. These sub-100 nm transient structures, which are stabilized far away from equilibrium, are believed to be functionally important in various physiological processes of the cell ranging from cell growth and movement to signal transduction and intercellular transport of proteins. 

Using advanced molecular simulation techniques and ideas/concepts from statistical mechanics and condensed matter physics, we are trying to address a few fundamental questions in the field of membrane spatiotemporal organization. This includes exploring the evolutionary rationale behind maintaining such complex lipid diversity despite the high metabolic expense of lipid homeostasis and identifying the build-in degeneracy in the membrane organization vis-à-vis related functionalities. 

Biological membranes undergo dramatic changes in curvature/shape during processes such as endocytosis, infection, immune response, the formation of organelles and division. These dynamic vesicular transport processes are often accompanied by tightly regulated leakage-free membrane fusion/fission reactions. Though topologically reversed, both reactions require that two bilayers are brought in close proximity against very high activation (hydration) energy barriers and possibly pass through several non-bilayer intermediates. The coupling between the conformation changes in the protein machinery and the orderly rearrangements of lipids leads to extreme membrane remodelling. The experimental difficulties associated with capturing the short-lived intermediates in protein conformations and membrane topologies point to the requirement for high-fidelity multiscale simulations. 

Currently, we are exploring the molecular mechanisms underlying the dynamin-assisted fission and Env-mediated HIV-1 fusion processes. We plan to apply the tools developed in the lab to explore the sub-millisecond kinetics and intermediates in complex vesicular transport processes such as those found in Golgi and Endoplasmic Reticulum.

To elucidate the disorder–function relationship in IDPs, it is important to determine the collection of 3-dimensional structures they adopt. However, generating high-resolution structural ensemble of IDPs is a daunting task and often not possible since information from biophysical experiments provide time and ensemble averaged data at low resolutions. In my laboratory, we apply an integrative approach of combining available biophysical data with advanced molecular simulations to extract the structural ensemble of IDPs at atomic resolutions. 

Currently, we are applying these integrative approach on several systems including (i) hnRNPA-GQ interaction, (ii) FUS-RNA interactions, (iii) Synuclein-Membrane interactions and (iv) APP-Membrane interaction. We have also developed coarse-grained models for proteins and RNA that form droplets/condensates and generating in-silico systems for membraneless organelles such as stress granule and P-bodies and studying their emergent properties under different mutant and environmental conditions.