Alladi Ramakrishnan Hall

Multiscale Modeling to unravel cellular and subcellular process in biological systems: Implication on signaling and exocytosis

Anirban Polley

How does a living organism composed of molecules have self-organized to do ‘engineering tasks’ such as efficient processing of information and control? We try to answer this fundamental question in the line: the complex biological processes can be understood from the properties of specific molecules which are building blocks of a living organism. To do this, we identify specific molecules involved in biological processes and determine their molecular structures, organization, and properties using multiscale modeling. We address important questions involving signaling and membrane fusion.

Previously, cell membrane was thought to be a bilayer-membrane separating the inner-cellular materials to protect cell from outside exhibiting lateral heterogeneities of lipid domains with no connection between domains in cell membrane to the inside of the cell. However, recently, works, both theoretical (Gourishankar et al., Cell 2012) and experimental (Goswami et al., Cell 2008), show that the outer leaflet lipid-tethered proteins (GPI-AP lipids) of the cell surface are organized as monomers and cholesterol sensitive nanoclusters, which are regulated by the organization of the underlying cortical actin and myosin below the cell membrane. Since GPI-APs reside on the outer leaflet of the bilayer membrane, the natural question is how the outer-leaflet GPI-APs couple to the cortical actin that abuts the inner leaflet of the cell membrane. We address these important issues using atomistic molecular dynamics (MD).

We also address the important biological process of membrane fusion reactions mediated by cellular fusion machinery whose core comprises of the SNARE proteins. During the fusion event, SNARE proteins are anchored to both the cell membrane and vesicle membrane by its flexible linkers and involve in pulling membranes into proximities, leading to membrane fusion. However, the mechanism is poorly understood. A highly coarse-grained MD simulation is developed to expose the cooperative behavior of SNAREs at the fusion site between a docked vesicle and target membrane.