Modeling the functional state of the reverse transcriptase of hepatitis B virus and its application to probing drug-protein interaction

BMC Bioinformatics

Research

Xiaojun Xu¹  James Lara¹  Guoliang Xia¹  Yury Khudyakov¹  Hong Thai¹  Lilia Ganova-Raeva¹  Anuj Gaggar²  Matthew Paulson²  Kathryn M. Kitrinos² 

[1] Division of Viral Hepatitis, National Center for HIV, Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, 30333, Atlanta, GA, USA;Gilead Sciences, Inc., Foster City, CA, USA;

关键词: Hybrid structure modeling;    Molecular dynamics (MD);    Solvated interaction energy (SIE);    Hepatitis B;    Tenofovir;    Drug resistance;    Reverse transcriptase;   

DOI  :  10.1186/s12859-016-1116-4

来源: Springer

【 摘 要 】

BackgroundHerein, 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.ResultsWe 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 (Mg2+) at the active site, whereby one Mg2+ 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.ConclusionThe 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.

【 授权许可】

CC BY   
© The Author(s). 2016