Insights into effect of the Asp25/Asp25MODIFIER LETTER PRIME protonation states on binding of inhibitors Amprenavir and MKP97 to HIV-1 protease using molecular dynamics simulations and MM-GBSA calculations

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/Asp25MODIFIER LETTER PRIME 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/Asp25MODIFIER LETTER PRIME protonated states highly affect conformational dynamics of two flaps in PR. The binding free energy calculations results suggest that the Asp25/Asp25MODIFIER LETTER PRIME 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/Asp25MODIFIER LETTER PRIME 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/Asp25MODIFIER LETTER PRIME protonation in the design of potent inhibitors towards PR.

Automated summary

The protonation states of Asp25/Asp25' significantly affect the conformational changes and inhibitor bindings of HIV-1 protease (PR). Dynamics analysis confirms the strong impact of Asp25/Asp25' protonation states on the conformational dynamics of the flaps in PR, while binding free energy calculations show a clear enhancement in inhibitor bindings due to these protonation states.