title: The dynamic properties of the Hepatitis C Virus E2 envelope protein unraveled by molecular dynamics.
abstract: Hepatitis C Virus (HCV) is one of the most persistent human viruses. Although effective therapeutic approaches have been recently discovered, their use is limited by the elevated costs. Therefore, the development of alternative/complementary strategies is an urgent need. The E2 glycoprotein, the most immunogenic HCV protein, and its variants represent natural candidates to achieve this goal. Here we report an extensive molecular dynamics (MD) analysis of the intrinsic properties of E2. Our data provide interesting clues on the global and local intrinsic dynamic features of the protein. Present MD data clearly indicate that E2 combines a flexible structure with a network of covalent bonds. Moreover, the analysis of the two most important antigenic regions of the protein provides some interesting insights into their intrinsic structural and dynamic properties. Our data indicate that a fluctuating β-hairpin represents a populated state by the region E2412-423. Interestingly, the analysis of the epitope E2427-446conformation, that undergoes a remarkable rearrangement in the simulation, has significant similarities with the structure that the E2430-442fragment adopts in complex with a neutralizing antibody. Present data also suggest that the strict conservation of Gly436 in E2 protein of different HCV genotypes is likely dictated by structural restraints. Moreover, the analysis of the E2412-423flexibility provides insights into the mechanisms that some antibodies adopt to anchor Trp437 that is fully buried in E2. Finally, the present investigation suggests that MD simulations should systematically complement crystallographic studies on flexible proteins that are studied in combination with antibodies.
authors.affiliation: a Institute of Biostructures and Bioimaging, C.N.R. , Naples I-80134 , Italy.|b Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche , Seconda Università di Napoli , Caserta 81100 , Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Barone
authors.affiliation: a Institute of Biostructures and Bioimaging, C.N.R. , Naples I-80134 , Italy.|b Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche , Seconda Università di Napoli , Caserta 81100 , Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Balasco
authors.affiliation: a Institute of Biostructures and Bioimaging, C.N.R. , Naples I-80134 , Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Autiero
authors.affiliation: a Institute of Biostructures and Bioimaging, C.N.R. , Naples I-80134 , Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Vitagliano
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D057134:Antibodies, Neutralizing / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus
keywords: antibody binding; conformational change; molecular dynamics; protein flexibility; viral proteins