Theory and Simulation of Membrane Deformations Orchestrated by Intracellular Molecular Assemblies

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

0853389 Radhakrishnan "This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)." Cell membranes and membrane based organelles actively mediate several intracellular signaling and trafficking decisions. A growing number of applications rely on cooperative interactions between molecular assemblies and membranes. Yet, the studies of membrane based and membrane mediated signaling are not considered core aspects of systems biology. While a coherent and complete description of cell membrane mediated signaling is not always possible by experimental methods, multiscale modeling and simulation approaches can provide valuable insights at nano/microscopic and mesoscopic scales. This project strives to develop a theoretical and computational platform for quantitatively describing how cell membrane topologies are actively mediated and manipulated by intracellular protein assemblies. Specifically, the proposal describes an integrated research and outreach program, involving a multiscale modeling study of Intracellular Endocytotic trafficking mechanisms, i.e., active transport mechanisms characterized by vesicle nucleation and budding of the cell membrane orchestrated by protein interaction networks. Intellectual Merit: The kinetic Monte Carlo time dependent Ginzburg Landau (KMC-TDGL) algorithm developed under the PIs previous research program represents a methodological advance because of its unique and innovative in its ability to combine two disparate phenomenological formalisms (Kinetic Monte Carlo and Time Dependent Ginzburg Landau) in order to obtain a unified picture of how curvature inducing proteins mediate cell membrane deformations under low membrane curvature. In this project, two new simulation approaches will be developed, which can predict protein induced membrane deformations in the high curvature limit. In Aim 1, the surface evolution method will be developed to predict minimum energy conformations of highly curved axis symmetric membrane structures relevant to the internalization of cell surface receptors through the process of clathrin mediated endocytosis. In Aim 2, a new method referred to as the local coordinate TDGL will be developed in order to extend the results of Aim 1 by computing finite temperature properties of arbitrarily (no imposed symmetry) curved membranes including the free energies of the system. In Aim 3, specific biological hypothesis governing the quantitative bioenergetics of clathrin mediated endocytosis will be explored. The proposed simulation framework will enable the development of a quantitative link between molecular driving forces and emergent functionality in endocytotic trafficking/transport networks. The proposed simulations will also provide rigorous foundations for differentiating intracellular trafficking fates on the basis of differences in molecular interactions due to homologous receptors or receptor mutations, which often gain prominence in dysfunctional trafficking pathways. Broader Impact: The proposed theory and modeling approaches are expected to create avenues for many novel applications in systems biology, pharmacology, and nanobiotechnology. The particular application to endocytosis explored here will provide a direct route to discern pathological cellular trafficking fates implicated in a variety of biomedical conditions such as cancer and schizophrenia. Complementing the interdisciplinary research program, the educational and outreach programs are constituted by rigorous and visionary research training for undergraduate students in engineering and biology. To achieve broader impact in complementing the undergraduate research experience, a three dimensional stereo environment for visualizing biomolecular structure and animations is established and utilized for the instruction of molecular modeling and simulation techniques at the undergraduate and graduate students.