Computational Studies of Biomolecular Structure and Function

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Many important biological processes, such as signalling, recognition, and transport, as well as infection and immune response, involve interactions between peptides or proteins and lipid. The detailed characterization of these processes is currently impeded by the difficulty in elucidating the structure of peptides and proteins in the anisotropic and chemically complex environment provided by lipid bilayers. For these reasons, structural studies of membrane proteins often employ detergent molecules, which mimic the chemical properties of lipid bilayers, to solubilize the proteins, making them more amenable to crystallization. However, at present there are no general methods for the experimental determination of membrane protein structure, underscoring the need for reliable predictive algorithms. A powerful approach to gain insight into the structure and function of biomolecules is to use computer simulations, but the scope of these studies is currently limited by the long time scales required to investigate the folding and self-assembly of proteins and peptides in lipid.In this proposal, we will address these limitations by combining novel sampling algorithms developed in our laboratory with massive computational resources awarded to us by Compute Canada. These extraordinary resources put us in a unique position to examine the interaction of peptides and proteins with lipid and detergent molecules in four different but complementary studies. In two of these projects, we will study how lipid and detergent self-assemblies solvate proteins and determine their fold. Reciprocally, in the other two studies, we will examine how the self-assembly of peptides affects the structure of lipid bilayers.This work will provide advanced computational tools for the much-needed prediction of membrane protein structure, and will help improve detergent-based approaches to elucidate the structure of membrane proteins experimentally. Just as important, the proposed studies will afford fundamental insight into the molecular basis for the action of antimicrobial peptides and the toxicity of peptides derived from prions implicated in "mad cow" and chronic wasting diseases, two serious threats to Canadian wildlife and agriculture.