Prediction of HCV E2 association with the host-cell chaperone, GRP78

Abstract

BackgroundHepatitis C Virus (HCV) is the main causative factor for liver cirrhosis and for the development of liver cancer. E2 is an HCV structural protein responsible for virus entry to the host cell. GRP78 is the master regulator of the unfolded protein response mechanism in the Endoplasmic Reticulum (ER) in normal conditions. Under the stress of HCV infection or carcinogenesis, GRP78 is upregulated. Consequently, it escapes the ER retention and translocates to the cytoplasm and over the plasma membrane. AimThis study aims to predict the binding mode of HCV E2 to GRP78 protein. MethodsDue to the high sequence and structural conservation between the C554–C566 region of HCV E2 and the Pep42, cyclic peptide that is reported to target GRP78, we propose that this region of E2 can be the recognition site. We predict the possible binding mode between HCV E2 and GRP78 by implementing molecular docking and molecular dynamics simulation to test such proposed binding. ResultsThe simulations reveal a stable and highly potent (−111.2 docking score) binding of the HCV E2 C554–C566 peptide to GRP78 substrate-binding domain β (SBDβ). Moreover, the full-length HCV E2 also exhibits high binding affinity to GRP78 SBDβ (score = −107.5 ± 3.1), which is better than the association of GRP78 and Pep42. ConclusionsDefining the compulsory mode between HCV E2 and GRP78 is significant, so it would be possible to interfere with such binding to reduce the viral infection.