Effective Energy Functions for Proteins in Lipid Membranes

Cuny City College, New York NY

Investigators

Abstract

Experimental work on membrane proteins faces many technical challenges. Therefore, computer modeling could have important impact in this field. Over the last few years the PI and his group have developed an implicit approach to modeling membrane proteins by adding to the force field a term that describes the solvation free energy of a protein in the heterogeneous membrane environment. In the previous grant period the implicit membrane model (IMM1) was extended to proteins with an aqueous pore and the effects of membrane surface charge and transmembrane voltage were incorporated. The model has been implemented into the CHARMM package and has been used to obtain insights into the forces that drive transmembrane helix association. Methods have also been developed for the calculation of absolute free energies for peptide-peptide association and peptide-membrane binding. The goals for the next grant period fall into two categories: methodology and applications. The methodological improvements include: a more accurate treatment of the solvation free energy of aligned dipoles, an improved treatment of the ionic sidechains incorporating long-range contributions, salt dependence, aqueous/nonaqueous environment dependence, examination of the need for a lipid alignment potential, incorporation of the dipole potential, and implicit solvent modeling of metal ions. The applications include: prediction and rationalization of the effect of mutations in membrane protein stability, studies of transmembrane helix association, prediction of the membrane binding mode of peripheral membrane proteins, and modeling the membrane insertion mechanism of colicin-type toxins. These studies will be carried out in collaboration with experimental groups. This research will be carried out at an institution where 60% of the students belong to underrepresented groups and several programs support the participation of undergraduates in research. The project will also train Ph.D. students in the Molecular Biophysics program at CUNY. The methods developed are available to the research community through the CHARMM program and can be used by researchers in academia and industry. They are useful to theoreticians and experimentalists alike and are applicable to important biological problems, such as membrane protein structure prediction, or understanding the mechanism of action of membrane proteins. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Theoretical and Computational Chemistry Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate.