Computational construction of hepatitis C virus core protein tertiary structure with various modeling methods

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver inflammation, in many cases, leading to liver fibrosis, cirrhosis, and cancer. HCV core protein is the structural protein responsible for HCV nucleocapsid formation. It was indicated that in addition to its primary virus capsid forming function, interactions between the HCV core protein and host cell surface receptors also found to contribute to systematic and local inflammation of the host. Therefore, a detailed understanding of interactions between HCV core protein and host cell receptors should be of great help in the development of strategies for the treatment of hepatitis induced by HCV. However, there is currently no experimentally resolved complete HCV core protein structure available for structure-based analysis on HCV core protein-host receptor interactions. In this study, we applied different computational tools for the construction of HCV core protein 3-dimensional structures. Multiple-template homology modeling and template-free modeling methods were applied, and several structural models of HCV core proteins with different lengths (amino acids 1-116, and 1-191) were yielded. Molecular dynamics (MD) simulations were used to refine the modeled structures. The modeled structures from different modeling methods were compared, and the root-mean-square-deviation (RMSD) and free energy for each modeled structure was calculated. We further applied molecular docking to study the interactions between HCV core protein and host Toll-like receptors (TLRs), the inflammation related receptors suggested to be major targeted of HCV core protein. Structures of TLR1/2 and TLR2/6 heterodimers were applied in our study. Based on the in silico investigations, inhibitory peptides for reducing host inflammation can then be designed for validations in cellular experiments.