Development and assessment of methods for studying membrane protein structure and function

National Institute Of Neurological Disorders And Stroke

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Abstract

Communication between cells and within organelles requires bypassing or traversing cellular membranes, which biology has typically solved using proteins with greasy surfaces that are happy to be surrounded by the lipid molecules that comprise such membranes. It is increasingly recognized that such membrane-embedded proteins can influence the shape of their lipid environment, as the lipids adjust to match the hydrophobic region on the protein surface. Less appreciated is that the extent and energetic cost of such deformations likely varies among different functional states of a protein, and thus, that they might contribute significantly to defining its mechanism. From the vantage point of the bilayer itself, the inclusion of certain lipids such as cholesterol can have a significant effect on its properties, such as resistance to bending or thinning. As computers have become more powerful, it has become possible to examine the interplay between protein and lipids through atomically-realistic molecular simulations. This year we have examined the role of cholesterol in modifying lipid behaviors, both in terms of the energetics and the behavior of the individual lipid molecules. By demonstrating how cholesterol affects unsaturated and saturated lipid types in different ways, we also resolved a controversy in the field. A future challenge is to compute the energetics of membranes while the proteins are present and undergoing their functions. To do so requires a careful description of the nature of the protein changes involved. Our lab has been actively involved in developing robust tools to interface with common molecular simulation software packages, and several recent enhancements to those tools were described in a review article, bringing these techniques to a wider audience and enhancing the understanding of a wide range of molecular problems.