Shukai Wang

Investigation of the structure and function of Vpu with all atom molecular dynamics simulations

Shukai Wang - 3rd year PhD


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 helps HIV virus infect the cell 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 VpuCyto (resid28-81) is related to CD4 down-regulation. However, the structure and the mechanism of the pore remain unknown.
To investigate this, a model has been constructed with a truncated Vpu7-25 in three different lipid bilayers (DLPC, DOPC and DMPC) using all-atom molecular dynamics with AMBER and lipid14 force fields. The results are reproducible and have strong agreement with the experimental observables such as tilt angles, kink points, bilayer thicknesses and area per lipid. This model is now being extended to incorporate one or multiple full-length NMR-solved Vpu strands in lipid bilayer to observe the pore formation. The goal is to study the mechanism of the pore formation at an atomic level of detail by application of multiple micro-second simulations using a full NMR derived model. This study will investigate changes of the pore when the environment of the bilayer is changed, including using different lipids and changing the symmetry of the bilayer. The results of this study will give indicative information of the mode of HIV infection, hence providing information for potential drug design.