Computer Modeling of the Interaction of Proteins with Membrane Surfaces: Insights into Subcellular Localization


The reversible binding of proteins to membranes is crucial to
many biological processes, such as signal transduction, vesicle
trafficking and viral assembly. Many of these "peripheral"
proteins contain lipid-interacting domains that recruit the
proteins to specific intracellular membranes in response to signals, such as an increase in cellular calcium or the production
of a phosphoinositide lipid. Our computational research and complementary experimental studies suggest that the binding of lipid-interacting domains to ligands, such as calcium ions or phosphoinositide head groups, dramatically alters the biophysical properties of the domains and that these changes are responsible for regulating membrane association. Further, it appears that various combinations of two physical factors, electrostatics and hydrophobicity, are major determinants of membrane binding. The finite difference Poisson-Boltzmann
(FDPB) method has proved extremely accurate in its ability
to account for many of the experimentally determined electrostatic properties of protein/membrane systems. This talk will focus on recent applications of the FDPB method to model the subcellular targeting of proteins to membrane surfaces. Our calculations of the physical forces between atomic-level models of proteins and phospholipid membranes provide insight, at the molecular level, into how different proteins are recruited to specific membranes and how proteins and lipids may be organized at membrane surfaces to facilitate the formation of macromolecular complexes. The overall computational approach we are developing provides a comprehensive framework with which to examine how proteins are designed to affect the wide range of membrane binding behaviors observed

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