ABSTRACT

The protonation states of two aspartic acids in the catalytic strands of HIV-1 protease (PR) remarkably affect bindings of inhibitors to PR. It is requisite for the design of potent inhibitors towards PR to investigate the influences of Asp25/Asp25ʹ protonated states on dynamics behaviour of PR and binding mechanism of inhibitors to PR. In this work, molecular dynamics (MD) simulations, MM-GBSA method and principal component (PC) analysis were coupled to explore the effect of Asp25/Asp25′ protonation states on conformational changes of PR and bindings of Amprenavir and MKP97 to PR. The results show that the Asp25/Asp25′ protonation states exert different impacts on structural fluctuations, flexibility and motion modes of PR. Dynamics analysis verifies that Asp25/Asp25ʹ protonated states highly affect conformational dynamics of two flaps in PR. The binding free energy calculations results suggest that the Asp25/Asp25ʹ protonated states obviously strengthen bindings of inhibitors to PR compared to the non-protonation state. Calculations of residue-based free energy decomposition indicate that the Asp25/Asp25ʹ protonation not only disturbs the interaction network of inhibitors with PR but also stabilizes bindings of inhibitors to PR by cancelling the electrostatic repulsive interaction. Therefore, special attentions should be paid to the Asp25/Asp25ʹ protonation in the design of potent inhibitors towards PR.

摘要

HIV-1 蛋白酶 (PR) 催化链中两种天冬氨酸的质子化状态显着影响抑制剂与 PR 的结合。研究Asp25/Asp25′质子化状态对PR动力学行为和抑制剂与PR结合机制的影响，是设计强效PR抑制剂的必要条件。在这项工作中，分子动力学 (MD) 模拟、MM-GBSA 方法和主成分 (PC) 分析相结合，以探索 Asp25/Asp25' 质子化状态对 PR 构象变化以及 Amprenavir 和 MKP97 与 PR 结合的影响。结果表明，Asp25/Asp25'质子化状态对PR的结构波动、柔韧性和运动模式产生不同的影响。动力学分析证实 Asp25/Asp25ʹ 质子化状态高度影响 PR 中两个皮瓣的构象动力学。结合自由能计算结果表明，与非质子化状态相比，Asp25/Asp25ʹ 质子化状态明显增强了抑制剂与 PR 的结合。基于残基的自由能分解计算表明，Asp25/Asp25ʹ 质子化不仅扰乱了抑制剂与 PR 的相互作用网络，而且还通过取消静电排斥相互作用来稳定抑制剂与 PR 的结合。因此，在设计针对 PR 的有效抑制剂时，应特别注意 Asp25/Asp25ʹ 质子化。基于残基的自由能分解计算表明，Asp25/Asp25ʹ 质子化不仅扰乱了抑制剂与 PR 的相互作用网络，而且还通过取消静电排斥相互作用来稳定抑制剂与 PR 的结合。因此，在设计针对 PR 的有效抑制剂时，应特别注意 Asp25/Asp25ʹ 质子化。基于残基的自由能分解计算表明，Asp25/Asp25ʹ 质子化不仅扰乱了抑制剂与 PR 的相互作用网络，而且还通过取消静电排斥相互作用来稳定抑制剂与 PR 的结合。因此，在设计针对 PR 的有效抑制剂时，应特别注意 Asp25/Asp25ʹ 质子化。