Computer simulation molecular dynamics (MD) calculations are proposed to complement experiments designed to elucidate structural characteristics of virus protein U (Vpu), an 81-residue protein which is encoded exclusively by human immunodeficiency virus type 1, HIV-1. Vpu has two distinct biological activities that are controlled by separate structural domains: Induction of the degradation of the CD4 receptor in the endoplasmic reticulum (ER) and augmentation of virus particle release from the plasma membrane. The former function involves the cytoplasmic (CYTO) sequences of Vpu and the latter the transmembrane (TM) domain. The goal of this project is to utilize new constant pressure and temperature MD methodologies to detail how, and where, HIV-1-specific Vpu interacts with cellular components. We have already published MD simulation results for the biologically relevant bilayer phase of the phospholipid dipalmitoylphosphatidylcholine (DPPC), which a well-recognized model membrane system. We have also recently carried out a simulation study of a membrane-spanning synthetic ion channel formed by a four- helix bundle of 21-residue peptides. We propose to build on these MD simulation results and explore the interactions of the hydrophobic Vpu TM domain peptide (Vpu 1-27) with a model membrane. Next, in light of their potential to act as biological channel for monvalent cations, we propose to determine the behavior of oligomers of the wild-type peptide Vpu 1-27 in a lipid bilayer. The MD technique will also be used to investigate the solution structure of the Vpu CYTO domain (peptide Vpu 32-81) to compare with contemporary experiments. To do so, we will carry out extensive MD simulation is aqueous and mixed hydrophilic and hydrophobic solvents. Finally, if the afore mentioned studies are successful, we will then attempt to characterize the behavior of HIV-1-specific Vpu in other membrane- mimetic environments including, bilayers, micelles and Langmuir monolayers. These computer simulation studies are designed to complement NMR and diffraction experiments, which will be carried out at UPENN and elsewhere, on HIV-1-specific Vpu.
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