SIMULATION OF SPONTANEOUS PEPTIDE INSERTION AND ASSEMBLY IN EPITHELIAL MEMBRANES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Spontaneous peptide insertion and self-assembly to form functional pores or channels in membrane are involved in a wide range of biological functions. Despite the great fundamental and biomedical importance, the precise mechanisms of the actions of these peptides remain poorly understood at molecular level. This limitation is related to both (1) a lack of suitable molecular modeling tools for simulating such complex processes and (2) lack of simple model peptide systems to systematically investigate various factors under controlled conditions to uncover the underlying basic principles. The long-term goal of the proposed studies is to develop a multi-scale computational framework and simultaneously exploit novel model peptide systems to obtain a molecular-level understanding of the physical principles of insertion and self-assembly of membrane peptides. The first aim is to develop a flexible coarse-grained (CG) protein-lipid force field that are both efficient and realistic enough to provide an accurate description of conformational equilibria of helical peptides and its dependence on membrane binding and peptide-peptide associations. The second aim is to utilize direct CG simulations and free energy calculations to understand how peptide sequence, solution conditions and lipid properties determine the spontaneous insertion and assembly of peptides in biological membranes. Specific roles of folding or assembly in insertion will be examined using two established model systems including TMX-1/TMX-3 and the GpA dimer. The main focus is to exploit amphipathic peptides derived the second transmembrane helix of the glycine receptor (M2GlyR) as a paradigm for understanding how folding, insertion and assembly are linked altogether for actions of helical membrane peptides.