IIIT Hyderabad Publications |
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Determination of the Native Oligomeric State of Vpu, Transmembrane Protein from HIV-1, and its Ion Channel ActivityAuthors: Siladitya Padhi,Harjinder Singh, Shahid Jameel,U Deva Priyakumar Conference: US Biophysical Society Thematic Meeting on "Lipid-Protein Interactions in Membranes: Implications for Health and Disease" Location CCMB Hyderabad Date: 2012-11-01 Report no: IIIT/TR/2012/141 AbstractVpu is an 81-residue protein encoded by human immunodeficiency virus type I (HIV-1) that facilitates viral release from host cells. The protein has a cytoplasmic domain and a helical transmembrane (TM) domain, of which the latter oligomerizes to form cation-specific ion channels. The number of TM domains that constitute the channel is still unclear, with experimental studies indicating the existence of a variety of oligomeric states. In this study, we have examined the possibility of Vpu to exist in tetra-, penta-, and hexameric states using comprehensive molecular dynamics (MD) simulations. By modeling the TM domain as an ideal α-helix, we carried out replica-exchange MD simulations in an implicit membrane environment for obtaining suitable starting structures, which were then subjected to extensive MD simulations in a fully hydrated lipid bilayer environment. The results show that the pentameric form is the most stable oligomeric state (the tetramer and hexamer models lose their initial channel-like structure), with helices in the pentamer being held together by strong van der Waals interactions. Hydrogen bonds between lipid headgroups and basic/hydrophilic residues on the protein are stronger in the pentamer than in the tetramer or the hexamer, indicating that these interactions might play a role in adhering the pentamer to the membrane. Free energy calculations using umbrella sampling technique have been performed to examine the potassium ion permeation through the pentameric pore. The results show a high free energy barrier corresponding to ion transport indicating weak ion channel activity in agreement with previous experimental biophysical studies. Full paper: pdf Centre for Computational Natural Sciences and Bioinformatics |
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