常珊等

摘要：对HTLV-1蛋白酶和抑制剂印地那韦的复合物进行了11 ns的分子动力学模拟，从分子整体、氢键、结合自由能及运动性等方面进行了分析。结果表明，动力学模拟使得体系更为松弛，但大部分氢键仍得到保持；疏水相互作用有利于HTLV-1蛋白酶和印地那韦的结合，关键残基主要分布在R10、L30～V39、V56～F67和W98～I1004个区域；结合自由能预测值与试验数据吻合较好。印地那韦结合仅能部分抑制HTLV-1蛋白酶的Flap、top-site以及两个exo-site位点柔性，解释了印地那韦的HIV-1 PR抑制活性为何略大于HTLV-1 PR。该研究为基于受体结构的抗HTLV-1药物研发打下了一定的结构和理论基础。

关键词：HTLV-1蛋白酶；印地那韦；分子动力学模拟；分子识别；结合自由能

中图分类号：O641.3；R969.1 文献标识码：A 文章编号：0439-8114（2015）12-3034-07

DOI：10.14088/j.cnki.issn0439-8114.2015.12.062

Molecular Dynamics Simulation of the Recognition between HTLV-1

Protease and Indinavir

CHANG Shan1，LIANG Li2，LIU Wei2，HU Jian-ping2，3，GOU Xiao-jun2

（1. Institute of Bioinformatics and Medical Engineering， Jiangsu University of Technology， Changzhou 213001， Jiangsu China；

2. Key Laboratory of Medicinal and Edible Plants Resources Development， Chengdu University， Chengdu 610106， China；

3. College of Chemistry， Leshan Normal University， Leshan 614004， Sichuan China）

Abstract： One 11 ns molecular dynamics simulation （MD） for the compocind system of Human T-cell leukemia virus type 1（HTLV-1） protease （PR） and its inhibitor indinavir was performed. The mutual recognition of the two molecules was analyzed from exploring the whole molecule，hydrogen bond，binding free energy and mobility，etc.After dynamics simulation，the system keeps more relaxed compared with the crystal structure， and most of the hydrogen bonds were still maintained. Both energy decomposition and free energy calculation showed that，hydrophobic interaction facilitates the association of HTLV-1 PR and indinavir，and key residues were mainly distributed in the four regions including R10，L30～V39，V56～F67 and W98～I100.Additionally，binding free energy prediction was in good agreement with the experimental data. Indinavir can only partially attenuate the flexibility of the flap，top-site and two exo-site in the PR system，which investigated why indinavir possess more HIV-1 PR inhibition ability than that of HTLV-1 PR. The study will provide some structural and theoretical basis for anti-HTLV-1 drug research based on the receptor structure.

Key words： HTLV-1 protease； Indinavir； molecular dynamics simulation； molecular recognition； binding free energy

I型人类T细胞白血病病毒（Human T-cell leukemia virus type 1，HTLV-1）参与了众多种类癌症，如成人T细胞白血病、热带痉挛性脊髓病以及HTLV-1相关的皮炎等[1，2]。目前，世界上约2 000万人感染了该病毒，临床治疗策略主要是采用细胞毒性化疗及干扰素、齐多呋定用药，开展抗HTLV-1的新型药物研发比较迫切[3]。

HTLV-1蛋白酶（Protease，PR）是同源蛋白二聚体，每个链由125个氨基酸残基，属于天冬氨酸蛋白酶家族[4，5]。HIV-1蛋白酶被认定为抗AIDS药物研发的一线靶点已有30年历史，目前FDA已经批准10多种HIV-1蛋白酶抑制剂药物上市[6]。而HTLV-1 PR和HIV-1 PR的序列同源性为28%，其中抑制剂结合区同源性更高，达到了45%。两类PR尽管具有相似的整体折叠，但是有不同的抑制剂结合特异性[7]。大部分HIV-1 PR抑制剂没有体现出抑制HTLV-1 PR的潜力，目前仅有HIV-1蛋白酶抑制剂印地那韦能够在较低的微摩尔级层次上抑制HTLV-1 PR活性，抑制常数为3.5 μm[8]。……