Effective Energy Functions for Proteins in Lipid Membranes

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The goal of this project is to develop an accurate and computationally efficient analytical implicit solvation model for membranes. An initial version of such a model (IMM1) has been recently proposed by extension of an implicit solvation model for aqueous proteins (EEF1). IMM1 predicts reasonable membrane insertion free energies, discriminates transmembrane from interfacially binding peptides, and gives stable molecular dynamics simulations of membrane proteins. This project aims to enhance the reliability and extend the applicability of IMM1 by testing some of its key assumptions and by incorporating several physical elements that are now missing. Specifically, this project involves: a. testing of the electrostatic screening model by comparison to continuum electrostatics calculations, b. extension to membrane proteins with an aqueous pore, such as porins or ion channels , c. addition of a separate lipid headgroup region with distinct solvent properties, d. incorporation of electrostatic effects arising from the dipole, surface, and transmembrane potentials, and e. calibration to available experimental data for quantitative prediction of binding free energies of peptides to membranes. The outcome of this work will be useful for understanding the energetic determinants of membrane protein structure, prediction of membrane protein structure from sequence, and studies of how conformational changes in membrane proteins are linked to their function. The models will be made available to the research community in both academia and the pharmaceutical industry. This research will be carried out at an institution where 60% of the students belong to underrepresented groups and undergraduates are heavily involved in research.