Effect of polarization on HIV-1protease and fluoro-substituted inhibitors binding energies by large scale molecular dynamics simulations.
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.
School of Physics and Electronics, Shandong Normal University, Jinan 250014, China.
Li L
LL
Duan
Department of Chemistry, East China Normal University, Shanghai 200062, China.|NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China.
T
T
Zhu
School of Physics and Electronics, Shandong Normal University, Jinan 250014, China.
Yu C
YC
Li
School of Physics and Electronics, Shandong Normal University, Jinan 250014, China.
Qing G
QG
Zhang
Department of Chemistry, East China Normal University, Shanghai 200062, China.|NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China.
John Z H
JZ
Zhang
D005453:Fluorescence; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D013997:Time Factors; D014867:Water / Q000737:chemistry
D017320:HIV Protease Inhibitors; D014867:Water; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1