Insights into effect of the Asp25/Asp25ʹ protonation states on binding of inhibitors Amprenavir and MKP97 to HIV-1 protease using molecular dynamics simulations and MM-GBSA calculations

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.

KEYWORDS:

• HIV-1 protease
• binding free energy
• protonation states
• molecular dynamics simulation
• MM-GBSA

Acknowledgements

The authors sincerely thank Prof. Jianzhong Chen (School of Science, Shandong Jiaotong University, Jinan 250357, China) for useful discussions and invaluable comments.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.1939149

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 12004216), and Shandong Provincial Natural Science Foundation, China (Grant No. ZR2020QA064).