title: Binding sensitivity of adefovir to the polymerase from different genotypes of HBV: molecular modeling, docking and dynamics simulation studies.
abstract: OBJECTIVE
  To investigate the molecular mechanisms underlying the influence of DNA polymerase from different genotypes of hepatitis B virus (HBV) on the binding affinity of adefovir (ADV).
  
  
  METHODS
  Computational approaches, including homology modeling, docking, MD simulation and MM/PBSA free energy analyses were used.
  
  
  RESULTS
  Sequence analyses revealed that residue 238 near the binding pocket was not only a polymorphic site but also a genotype-specific site (His238 in genotype B; Asn238 in genotype C). The calculated binding free-energy supported the hypothesis that the polymerase from HBV genotype C was more sensitive to ADV than that from genotype B. By using MD simulation trajectory analysis, binding free energy decomposition and alanine scanning, some energy variation in the residues around the binding pocket was observed. Both the alanine mutations at residues 236 and 238 led to an increase of the energy difference between genotypes C and B (ΔΔG(C-B)), suggesting that these residues contributed to the genotype-associated antiviral variability with regard to the interaction with ADV.
  
  
  CONCLUSIONS
  The results support the hypothesis that the HBV genotype C polymerase is more sensitive to ADV than that from genotype B. Moreover, residue N236 and the polymorphic site 238 play important roles in contributing to the higher sensitivity of genotype C over B in the interaction with ADV.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Du
authors.forename: Xian
authors.initials: X
authors.lastname: Liu
authors.forename: Qian-cheng
authors.initials: QC
authors.lastname: Shen
authors.forename: Ai-long
authors.initials: AL
authors.lastname: Huang
authors.forename: Ming-yue
authors.initials: MY
authors.lastname: Zheng
authors.forename: Xiao-min
authors.initials: XM
authors.lastname: Luo
authors.forename: Hua-liang
authors.initials: HL
authors.lastname: Jiang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006509:Hepatitis B / Q000821:virology*; D006515:Hepatitis B virus / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology*; D016415:Sequence Alignment; D013816:Thermodynamics
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; C053001:adefovir; D004259:DNA-Directed DNA Polymerase; D000225:Adenine