The interaction of peptides and proteins with lipid membranes is key to many biological processes. Over the past years the PI and his group have developed an implicit membrane model (IMM1) that describes protein-membrane interactions through a solvation free energy term. The model accounts for the effects of surface, transmembrane, and dipole potential and can also model pores of different shapes, making it the most comprehensive model of its kind. The model has been used to address a number of interesting biological problems, including the determination and analysis of membrane-bound protein structures, transmembrane helix association, and membrane insertion of toxins. In this project, this model will be extended in a number of directions. An improved treatment of the lipid headgroup region will yield more accurate results for interfacial binding. Incorporating lateral pressure effects will allow accounting for the effects of lipid composition. Extending the model to curved membranes will allow the study of the mechanism of membrane curvature sensing and generation, which are key in processes like endocytosis or protein sorting. In addition, implicit solvation models for detergents will be developed, aiming to obtain structural information on detergent-peptide complexes, characterize the SDS-denatured state, and study the effect of lipid environment on peptide conformation. At the same time, these methods will be applied to important biological problems, including the structure of the hemagglutinin fusion peptide in bilayers, in micelles, and in implicitly modeled fusion stalks, the conformation of á-synuclein in membranes of different curvature, and the open channel state of colicins. Collaborations with experimental groups will provide synergy between theory and experiment.
This research will be carried out at an institution where the majority of the students belong to underrepresented groups and several programs support the participation of undergraduates in research. Several minority students at the high school, undergraduate, or graduate level have participated so far in the research carried out in this lab. This project will train Ph.D. students in the Molecular Biophysics subdiscipline of the Chemistry and Biochemistry doctoral programs at the City University of New York. The methods developed in this lab are available to the research community through the CHARMM program and can be used by theoreticians and experimentalists in academia and industry to address important biological problems, such as membrane protein structure prediction or understanding the mechanism of action of membrane proteins. This project is jointly supported by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Physics Division.
