title: Modeling the functional state of the reverse transcriptase of hepatitis B virus and its application to probing drug-protein interaction.
abstract: BACKGROUND
  Herein, the predicted atomic structures of five representative sequence variants of the reverse transcriptase protein (RT) of hepatitis B virus (HBV), sampled from patients with rapid or slow response to tenofovir disoproxil fumarate (TDF) treatment, have been examined to identify structural variations between them in order to assess structural and functional properties of HBV-RT variants associated with the differential responses to TDF treatment.
  
  
  RESULTS
  We utilized a hybrid computational approach to model the atomistic structures of HBV-RT/DNA-RNA/dATP and HBV-RT/DNA-RNA/TFV-DP (tenofovir diphosphate) complexes with the native hybrid DNA-RNA substrate in place. Multi-nanosecond molecular dynamics (MD) simulations of HBV-RT/DNA-RNA/dATP complexes revealed strong coupling of the natural nucleotide substrate, dATP, to the active site of the RT, and the differential involvement of the two putative magnesium cations (Mg(2+)) at the active site, whereby one Mg(2+) directly bridges the interaction between dATP and HBV-RT and the other serves as a coordinator to maintain an optimal configuration of the active site. Solvated interaction energy (SIE) calculated in MD simulations of HBV-RT/DNA-RNA/TFV-DP complexes indicate no differential binding affinity between TFV-DP and HBV-RT variants identified in patients with slow or rapid response to TDF treatment.
  
  
  CONCLUSIONS
  The predicted atomic structures accurately represent functional states of HBV-RT. The equivalent interaction between TFV-DP and each examined HBV-RT variants suggests that binding affinity of TFV-DP to HBV-RT is not associated with delayed viral clearance.
authors: Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, 30333, USA.
authors: Xiaojun
authors: X
authors: Xu
authors: Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, 30333, USA.
authors: Hong
authors: H
authors: Thai
authors: Gilead Sciences, Inc., Foster City, CA, USA.
authors: Kathryn M
authors: KM
authors: Kitrinos
authors: Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, 30333, USA.
authors: Guoliang
authors: G
authors: Xia
authors: Gilead Sciences, Inc., Foster City, CA, USA.
authors: Anuj
authors: A
authors: Gaggar
authors: Gilead Sciences, Inc., Foster City, CA, USA.
authors: Matthew
authors: M
authors: Paulson
authors: Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, 30333, USA.
authors: Lilia
authors: L
authors: Ganova-Raeva
authors: Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, 30333, USA.
authors: Yury
authors: Y
authors: Khudyakov
authors: Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, 30333, USA. xzl5@cdc.gov.
authors: James
authors: J
authors: Lara
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D004347:Drug Interactions; D024882:Drug Resistance, Viral / Q000235:genetics; D006515:Hepatitis B virus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007477:Ions; D008274:Magnesium / Q000494:pharmacology; D008958:Models, Molecular; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D000068698:Tenofovir / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D007477:Ions; D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins; D000068698:Tenofovir; D012194:RNA-Directed DNA Polymerase; D008274:Magnesium
keywords: Drug resistance; Hepatitis B; Hybrid structure modeling; Molecular dynamics (MD); Reverse transcriptase; Solvated interaction energy (SIE); Tenofovir