Multiscale Modeling of Protein Mediated Membrane Phase and Dynamical Behavior

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Proposal Number: CBET: 0730955 Principal Investigator: Ravi Radhakrishna University/Institution: University of Pennsylvania Title: Multiscale Modeling of Protein Mediated Membrane Phase and Dynamical Behavior Several design problems in nano-bio-technology are governed by a complex interplay of fundamental processes at multiple length and timescales. While a coherent and complete description of these processes is not always possible by experimental methods, modeling and simulation approaches can provide valuable insights at atomic, mesoscale, and macroscale resolutions through multiscale modeling approaches. This project strives to achieve a multiscale description of equilibrium and dynamic processes associated with a class of complex fluids with nanoscale inclusions, namely, biological membranes mediated by membrane associating and membrane bound proteins. The primary objective is to develop a multiscale technology and apply it to achieve a quantitative and experimentally testable description how interactions at a molecular level lead to manifestation of properties at the mesoscopic level (approaching the length and timescales relevant to a biological cell). Intellectual Merit: At the core of the methodological advance is the proposal to devise a new strategy for integrating two different phenomenological approaches, namely, a field theoretic (continuum) description for the membrane dynamics and a discrete (lattice) description for the protein dynamics, a combination that results in a new computational technology with the power to describe dynamical behavior in complex processes involving multiple spatial and temporal scales. The KMC-TDGL algorithm is unique and innovative in its ability to combine two disparate phenomenological formalisms (Kinetic Monte Carlo and Time Dependent Ginzburg Landau) in such a manner as to allow for a two-way coupling between the two methods. The combined approach will be applied to obtain a unified picture of how curvature inducing proteins mediate cell membrane dynamics. The method will be validated at two levels. (1) Phenomenological potentials of interaction at the nanoscopic scale will be validated and parameterized by atomic-level molecular dynamics simulations. (2) The KMC-TDGL simulations will also be critically evaluated by comparing the predictions directly with well-characterized experiments. This will enable the proposed unified approach to be founded on the basis of atomic level interactions while retaining the capability of describing dynamical and thermodynamic properties at the mesoscopic level. The multiscale approach to be developed is generalizable and applicable to a variety of biophysical and biochemical processes such as protein-mediated biological phenomena occurring on the cell membrane. These include biological adhesion mediated by protein-protein interaction, endocytosis (internalization mechanism for proteins or nanocarriers), raft formation (microdomains in the lipid bilayer phase that are enriched in cholesterol), or biogenesis of caveolae (flask shaped vesicular structures formed in the membranes). Broader Impact: The approach is also generalizable to processes outside of membrane biophysics such as DNA dynamics, crystal growth kinetics etc. Therefore, it is likely to have a significant impact in enabling fundamental scientific discoveries at the nanobio interface in the disciplines of pharmaceutical science, synthetic biology, nano-bio-technology, and systems biology. Complementing the interdisciplinary research program in engineering and quantitative biology, the proposed educational and outreach programs will leverage existing channels at the University of Pennsylvania, as well as introduce new avenues to build a rigorous and visionary integrated program encompassing theoretical, computational, and experimental technologies. The research program will also provide direct impact and impart strong scientific and technological value not only to several graduate students and undergraduate students through the research and teaching activities of the PI, but also to academic scholars nationally and internationally through the proposed activities for dissemination and international collaboration.