Effect of polarization on HIV-1protease and fluoro-substituted inhibitors binding energies by large scale molecular dynamics simulations

Li L. Duan,T. Zhu,Yu C. Li,Qing G. Zhang,John Z. H. Zhang

doi:10.1038/srep42223

Abstract

Molecular dynamics simulations in explicit water are carried out to study the binding of six inhibitors to HIV-1 protease (PR) for up to 700 ns using the standard AMBER force field and polarized protein-specific charge (PPC). PPC is derived from quantum mechanical calculation for protein in solution and therefore it includes electronic polarization effect. Our results show that in all six systems, the bridging water W301 drifts away from the binding pocket in AMBER simulation. However, it is very stable in all six complexes systems using PPC. Especially, intra-protease, protease-inhibitor hydrogen bonds are dynamic stabilized in MD simulation. The computed binding free energies of six complexes have a significantly linear correlation with those experiment values and the correlation coefficient is found to be 0.91 in PPC simulation. However, the result from AMBER simulation shows a weaker correlation with the correlation coefficient of −0.51 due to the lack of polarization effect. Detailed binding interactions of W301, inhibitors with PR are further analyzed and discussed. The present study provides important information to quantitative understanding the interaction mechanism of PR-inhibitor and PR-W301 and these data also emphasizes the importance of both the electronic polarization and the bridging water molecule in predicting precisely binding affinities.

Highlights

Since the beginning of the acquired immune deficiency syndrome (AIDS) pandemic, approximately 78 million people worldwide have been infected and close to 39 million have died of AIDS-related causes
The dynamics simulation shows that the bridging water W301 drifts away from the binding pocket in the standard AMBER simulation
This can be explained that the polarized hydrogen bond interacts to the W301, which lengthens its stability in the binding pocket

Summary

Introduction

Since the beginning of the acquired immune deficiency syndrome (AIDS) pandemic, approximately 78 million people worldwide have been infected and close to 39 million have died of AIDS-related causes. The crystal water molecule W301 has an important role in the opening and closing of the flaps as well as increasing the affinity between protein and inhibitor It is observed in almost all PR and inhibitor complex and forms four hydrogen bonds with inhibitor and the residue Ile50/Ile50′, this bridges the flaps and inhibitor[7]. The incorporation of polarization effects into the force field can improve the quality of force fields[29,30,31,32] It may provide an accurate and reliable description about the binding of inhibitor-PR in which the active site is mainly made up of polar amino acid residues.

Methods

Results

Conclusion