A computer model for the membrane binding of HIV-1 Gag

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DESCRIPTION (provided by applicant): The overall goal of this research is to develop computational models for how type C retroviruses interact with the cytosolic surface of the plasma membrane of infected cells during viral assembly. A myristate and cluster of basic residues in the N-terminal matrix (MA) sequence are required for membrane association of the Gag polyprotein from human immunodeficiency virus type 1 (HIV-1); other retroviral MAs contain similar motifs. Therefore, the first specific aim is to test the hypothesis that nonspecific electrostatic and hydrophobic interactions provide enough energy to account for the membrane binding of retroviral MAs of known structure by using continuum electrostatic models to calculate their physical interactions with atomic models of phospholipid bilayers. MAs share the same structural fold in spite of very low sequence identity. In each MA structure, a cluster of basic residues is located on the surface of the molecule even though these residues are not conserved in linear sequence space. Thus, MAs appear to share structural and electrostatic homology in the absence of sequence similarity. The second specific aim is to test the generality of this observation by building models for MAs of unknown structure and calculating their biophysical properties. In order to facilitate new discoveries about MA function, e.g. the possibility that electrostatic interactions play a general role in Gag targeting, the third specific aim is to construct a relational database which combines computational, experimental and genomic information on MAs. HIV requires a fluid membrane envelope for its structural integrity and is, thus, not amenable to traditional structural techniques. This proposal lays the foundation for future computational work on a comprehensive computer model of retroviral assembly and structure. The research is highly innovative because by focusing on questions that are not easily addressed by other methods, it will provide molecular models of the protein/membrane interactions crucial to viral assembly which can be used to suggest novel therapeutic approaches to disrupting the production of progeny virions.