中文摘要：

为了研究别构小分子2-乙酸苯并噻吩（2FX）在HIV-1蛋白酶与抑制剂结合中的作用,利用分子动力学方法分别对未结合和结合2FX的HIV-1蛋白酶抑制剂体系进行了100 ns的模拟,模拟计算中对每种体系均采用两种新的分子力场ff99SBildn和ff12SB.研究了2FX对体系构象的影响和两体系在不同力场下的动力学行为,分析了两体系的均方根偏差和残基的B因子,比较了计算结构和晶体结构,最后采用MM-PB/GBSA两种方法计算了两体系的结合自由能.研究表明,两种力场计算的结果虽有差异,但都说明2FX的结合导致蛋白酶构象的变化,使得体系更加稳定,尤其是flap的柔性减弱,使得蛋白酶和抑制剂的结合更牢固;另外,还发现ff12SB力场动力学过程更稳定.研究结果有助于为设计新的别构抑制剂提供理论依据.

英文摘要：

In order to study the role of allosteric fragment 2-ylacetic acid-benzothiophene （2FX） in the binding of HIV-1 protease （PR） and inhibitor, the molecular dynamics simulations of 100 nanoseconds have been successfully performed on two systems of HIV-1 protease and inhibitor, respectively, one of which 2FX is attached to and another is not. Both types of new force fields, ff99SBildn and ffl2SB, and GPU parallel computing technology have been used for each of the two systems in the simulations. By investigating the influence of 2FX on the protease, it is found that the binding of 2FX induces a con- formational change of the protease. The dynamics behaviors of the two systems under the two force fields are compared with the VMD visualization software and it is found that, to a certain extent, there exist differences between those from the differ- ent forces. The root-mean-square deviations （RMSD）, the B-factors of the two systems, and structure superposition between the calculated and X-ray crystal structures, which display that the system with 2FX has a more stable dynamics process and the vibration extent of the residues decreases, indicate that the 2FX bound in the protease can stabilize the system. The bind- ing free energies have been calculated using the two force fields and using two methods, MM-PB/GBSA, respectively. The resulting free energy values, ff99SBildn： --70.52 and --68.42 kcal/mol （PB）, --86.72 and --89.40 kcal/mol （GB）; ffl2SB： --75.40 and --77.68 kcal/mol （PB）, --87.01 and --93.75 kcal/mol （GB）, 2FX-system being generally of greater magnitudes, also suggest the allosteric fragment stabilizes the binding of inhibitor and PR. The present results, despite the discrepancies between those from the two different force fields, demonstrate that the allosteric fragment 2FX unambiguously gives rise to subtle changes of structure of the PR and make the inhibitor and PR combine more firmly. In particular, it is clear that the fragment acts to weaken the flexibility of the flap,