Transmembrane (TM) proteins are essential components in biological membranes. They have a great range of activities and are integral for membrane functionality. Currently 50% of drugs target transmembrane proteins and yet little is known about their structure-function relationships. Vpu is an accessory type-I integral TM protein in the HIV virus. It is believed that Vpu assists the HIV virus to infect cells, even at low viral load, by forming an ion-channel/pore-like structure. Previous work has shown that VpuTM (resid2-27) at the N-terminal is involved in this pore formation and that the VpuCyto (resid28-81) is related to CD4 down-regulation. However, the structure and the mechanism of the pore remain unknown. By simulating TM proteins using molecular dynamics it will be possible to learn more about the structures and to design drug molecules to specifically bind to a given protein without the need for costly experimental trials and assays.<br/><br/>A methodology for conducting all-atom molecular dynamics simulations of TM proteins has been developed and applied in simulations of truncated Vpu7-25 in three different lipid bilayers (DLPC, DOPC and DMPC) using the AMBER-99SB and lipid14 forcefields. The method results are reproducible and show strong agreement with experimental tilt angles, kink points, bilayer thicknesses and areas per lipid. To investigate the pore formation, full-length NMR-resolved Vpu strands were simulated in the lipid bilayer. This is the first study of the pore formation mechanism using simulations over 1 micro-second and a fully-NMR-resolved model. This study also investigates the effect of changing lipids on pore formation. The results of this study advance the understanding of the pore formation mechanism of Vpu during HIV infection, and hence provide a foundation for future drug design studies.

All-atom molecular dynamics of an ion-channel formed by viral protein U in lipid bilayers

255th National Meeting (2018)

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