Quantum computational analysis for drug resistance of HIV-1 reverse transcriptase to nevirapine through point mutations
Quantum computational analysis for drug resistance of HIV-1 reverse transcriptase to nevirapine through point mutations
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DOI：
10.1002/prot.20578
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发表时间：
2005-11-01
影响因子：
2.9
通讯作者：
Zhang, JZH
中科院分区：
文献类型：
--
作者：
He, X;Mei, Y;Zhang, JZH
用量子化学方法研究了奈韦拉平与HIV-1逆转录酶（RT）及单点突变体Lys 103-> Asn（K103 N）和Tyr 181-> Cys（Y181 C）的相互作用。在这项研究中，整个系统的HIV-1 RT/奈韦拉平复杂的超过15,000个原子明确治疗使用最近开发的MFCC（分子分馏共轭帽）的方法。在Hartree-Fock和DFT水平上对蛋白质-药物相互作用能进行了量子计算。RT-奈韦拉平相互作用能是在蛋白质数据库（PDB）中HIV-1 RT/奈韦拉平复合物的晶体结构给出的固定几何结构下计算的。本计算提供了一个量子力学相互作用谱，明确显示奈韦拉平和RT的单个氨基酸片段之间的相互作用能。详细的相互作用是负责两个主要的RT突变的耐药性的基础上阐明的计算分析结合复合物的晶体结构。本研究结果提供了一个定性的分子认识HIV-1 RT耐药奈韦拉平，并提供了有用的指导，在设计改进的抑制剂，更好地抵抗RT突变。
Quantum chemical calculation has been carried out to analyze binding interactions of nevirapine to HIV-1 reverse transcriptase (RT) and single point mutants Lys103 -> Asn (K103N) and Tyr181 -> Cys (Y181C). In this study, the entire system of HIV-1 RT/nevirapine complex with over 15,000 atoms is explicitly treated by using a recently developed MFCC (molecular fractionation with conjugate caps) approach. Quantum calculation of protein-drug interaction energy is performed at Hartree-Fock and DFT levels. The RT-nevirapine interaction energies are computed at fixed geometries given by the crystal structures of the HIV-1 RT/nevirapine complexes from protein data bank (PDB). The present calculation provides a quantum mechanical interaction spectrum that explicitly shows interaction energies between nevirapine and individual amino-acid fragments of RT. Detailed interactions that are responsible for drug resistance of two major RT mutations are elucidated based on computational analysis in relation to the crystal structures of binding complexes. The present result provides a qualitative molecular understanding of HIV-1 RT drug resistance to nevirapine and gives useful guidance in designing improved inhibitors with better resistance to RT mutation.