Cholesterol modulating the orientation of His17 in hepatitis C virus p7(5a) viroporin -A molecular dynamic simulation study

摘要

Protein p7 of HCV is a 63 amino acid channel forming membrane protein essential for the progression of viral infection and the sensitivity of this channel to small-molecule inhibitors renders p7 a potential target for novel therapies against HCV infection. Previous biochemical experiments suggested that the His 17 of p7 is a pore-lining residue and solvated-exposed to participate in channel gating. However, a recent NMR structural identification of the p7 hexamer in dodecylphosphocholine (DPC) micelles indicated that the His17 is embedded into the protein matrix. In this work, we performed molecular dynamic simulations to bridge the controversial observations. Our results illustrated that by incorporating the cholesterol into DOPC membranes to mimic an actual membrane-like composition, the orientation of His17 in the hexameric bundles spontaneously access to the central pore region, indicating a versatile property of the p7 viroporin conformation that could be voluntarily influenced by its surrounding environments.