title: Computational study on the inhibitor binding mode and allosteric regulation mechanism in hepatitis C virus NS3/4A protein.
abstract: HCV NS3/4A protein is an attractive therapeutic target responsible for harboring serine protease and RNA helicase activities during the viral replication. Small molecules binding at the interface between the protease and helicase domains can stabilize the closed conformation of the protein and thus block the catalytic function of HCV NS3/4A protein via an allosteric regulation mechanism. But the detailed mechanism remains elusive. Here, we aimed to provide some insight into the inhibitor binding mode and allosteric regulation mechanism of HCV NS3/4A protein by using computational methods. Four simulation systems were investigated. They include: apo state of HCV NS3/4A protein, HCV NS3/4A protein in complex with an allosteric inhibitor and the truncated form of the above two systems. The molecular dynamics simulation results indicate HCV NS3/4A protein in complex with the allosteric inhibitor 4VA adopts a closed conformation (inactive state), while the truncated apo protein adopts an open conformation (active state). Further residue interaction network analysis suggests the communication of the domain-domain interface play an important role in the transition from closed to open conformation of HCV NS3/4A protein. However, the inhibitor stabilizes the closed conformation through interaction with several key residues from both the protease and helicase domains, including His57, Asp79, Asp81, Asp168, Met485, Cys525 and Asp527, which blocks the information communication between the functional domains interface. Finally, a dynamic model about the allosteric regulation and conformational changes of HCV NS3/4A protein was proposed and could provide fundamental insights into the allosteric mechanism of HCV NS3/4A protein function regulation and design of new potent inhibitors.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xue
authors.affiliation: Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou, China.
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou, China ; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000998:Antiviral Agents / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases