title: The NS4A Cofactor Dependent Enhancement of HCV NS3 Protease Activity Correlates with a 4D Geometrical Measure of the Catalytic Triad Region.
abstract: We are developing a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active site of HCV NS3 proteases, in relation to their catalytic activity. In our previous work, the 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) yielded divergent, gradual and genotype-dependent, 4D conformational instability measures, which strongly correlate with the known disparate catalytic activities among genotypes. Here, the correlation of our 4D geometrical measure is extended to intra-genotypic alterations in NS3 protease activity, due to sequence variations in the NS4A activating cofactor. The correlation between the 4D measure and the enzymatic activity is qualitatively evident, which further validates our methodology, leading to the development of an accurate quantitative metric to predict protease activity in silico. The results suggest plausible "communication" pathways for conformational propagation from the activation subunit (the NS4A cofactor binding site) to the catalytic subunit (the catalytic triad). The results also strongly suggest that the well-sampled (via convergence quantification) structural dynamics are more connected to the divergent catalytic activity observed in HCV NS3 proteases than to rigid structures. The method could also be applicable to predict patients' responses to interferon therapy and better understand the innate interferon activation pathway.
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Illinois, United States of America.
authors.forename: Hamzah A
authors.initials: HA
authors.lastname: Hamad
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Illinois, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Thurston
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Illinois, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Teague
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Illinois, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Ackad
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Illinois, United States of America.|Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Yousef
mesh_terms: D000595:Amino Acid Sequence; D002384:Catalysis; D016174:Hepacivirus / Q000201:enzymology*; D017386:Sequence Homology, Amino Acid; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus