Decoding molecular mechanism underlying binding of drugs to HIV-1 protease with molecular dynamics simulations and MM-GBSA calculations

ABSTRACT

HIV-1 protease (PR) is thought to be efficient targets of anti-AIDS drug design. Molecular dynamics (MD) simulations and multiple post-processing analysis technologies were applied to decipher molecular mechanism underlying binding of three drugs Lopinavir (LPV), Nelfinavir (NFV) and Atazanavir (ATV) to the PR. Binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA) suggest that compensation between binding enthalpy and entropy plays a vital role in binding of drugs to PR. Dynamics analyses show that binding of LPV, NFV and ATV highly affects structural flexibility, motion modes and dynamics behaviour of the PR, especially for two flaps. Computational alanine scanning and interaction network analysis verify that although three drugs have structural difference, they share similar binding modes to the PR and common interaction clusters with the PR. The current findings also confirm that residues located interaction clusters, such as Asp25/Asp25ʹ, Gly27/Gly27ʹ, Ala28/Ala28ʹ, Asp29, Ile47/Ile47ʹ, Gly49/Gly49ʹ, Ile50/Ile50ʹ, Val82/Val82ʹ and Ile84/Ile84, can be used as efficient targets of clinically available inhibitors towards the PR.

KEYWORDS:

• HIV-1 protease
• binding free energy
• molecular mechanism
• MM-GBSA
• computational alanine scanning

Acknowledgements

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). 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 authors.

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.1979647.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [Grant No. 12004216]; Shandong Provincial Natural Science Foundation, China [Grant No. ZR2020QA064].