COMPUTATIONAL ANALYSIS OF PEPTIDE/LIPID INTERACTIONS AND AT MEMBRANE SURFACES

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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. Keywords: Finite difference Poisson-Boltzmann, protein/lipid interactions, subcellular targeting, electrostatics, membranes Abstract: This is a request for an extension of the grant we were awarded beginning 10/01/04 by the NSF High-performance Computing and TeraGrid Sites Allocations Committee, number MCB030028 (also listed as PSC grant MCB020050P) for the period 10/01/04-09/30/05, with the possibility of the award continuing for three years. While this period has been an extremely productive one, we have significantly overdrafted this grant. As PI for this project, I take full responsibility for this and can only offer the explanations that 1) the resource was so well-suited to our computational needs that students and postdocs used it for additional projects not included in the original proposal, and 2) I was very ill this past year (including a major surgery and two hospital stays) and did not adequately impress upon the users in my lab the protocol for responsible usage. I deeply apologize for this situation, especially the latter, and it is my hope that this report, which briefly describes our increased usage and a new stringent usage protocol, will help convince the Allocations Committee to forgive the overdraft and grant us an extension of our current allocation for this period. Specifically, we are humbly asking for an additional 20,000 SU on the PSC HP Marvel above and beyond the ~ 100,000 SU already used to date and that we may still retain access to our TeraGrid Wide Roaming SUs. We would greatly appreciate a second chance and hope that we may be granted continued access to the HP Marvel through 09/30/04. I have simultaneously submitted a Progress Report which provides more detail on our current projects which are being supported by our NSF High-performance Computing award. This report also describes our productivity during this period. We have been using the TeraGrid PSC HP Marvel with great success in modeling multi-component macromolecular complexes of significant biological relevance. This resource is, thus, crucial to the success of our research program. As described in our original proposal, the long term objective of the proposed research is to characterize the structural and energetic basis for the binding of peripheral membrane proteins to phospholipid membranes and, in turn, to better understand the biophysical basis of membrane-mediated events in cells. The finite difference Poisson-Boltzmann (FDPB) method has proved extremely accurate in its ability to account for many of the experimentally determined electrostatic properties of protein/membrane systems, and we are applying this continuum method along with a semi-empirical approach to characterize the hydrophobic contribution to membrane association to the following problems. The specific aims of our original proposal seek to characterize the membrane binding behaviors of a collection of carefully selected families of peripheral membrane proteins. While each family has unique membrane binding behaviors, their membrane association can ultimately be described by the interplay of electrostatic and hydrophobic interactions. During the past year we have built on previous methodology to more accurately depict the physical properties of protein/membrane systems, and we have expanded our focus to include other protein families with their own interesting membrane binding characteristics. (Progress related to our original aims and proposed new projects are provided in our Progress Report.) A fundamental question in cell biology is how the recruitment of proteins to different cellular membranes is achieved and regulated. The major research objective in our lab is to use computational approaches to understand the physical, molecular and structural bases of membrane targeting in cellular signaling processes and in viral assembly. A detailed dissection of the molecular mechanisms underlying the membrane binding behaviors of a wide range of peripheral proteins would facilitate the understanding of subcellular targeting as well as the rational design of drugs that inhibit membrane binding in biological processes that lead to disease states.