Some insights into mechanism for binding and drug resistance of wild type and I50V V82A and I84V mutations in HIV-1 protease with GRL-98065 inhibitor from molecular dynamic simulations

Hu, Guodong; Zhu, Tong; Zhang, Shaolong; Wang, Dunyou

doi:10.1016/j.ejmech.2009.09.048

Cited by 30 publications

(10 citation statements)

References 35 publications

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“…The MM/PBSA method, integrated in AMBER 10, was employed to predict the binding free energy. The MM/PBSA method is a versatile tool for calculating the binding free energies of a given proteineligand complex or proteineprotein/peptide complex, which incorporates the effects of thermal averaging with a force field/continuum solvent models to post-process a series of representative snapshots from MD trajectories (Hu et al, 2010). The binding free energies (DG bind ) were computed according to the following equations.…”

Section: Binding Free Energy Calculationmentioning

confidence: 99%

Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance

Zhang

Yao

Yang³

et al. 2012

Insect Biochemistry and Molecular Biology

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Section: Binding Free Energy Calculationmentioning

confidence: 99%

Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance

Zhang

Yao

Yang³

et al. 2012

Insect Biochemistry and Molecular Biology

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“…At present, QM/MM method and MD simulations have been combined to successfully study the inhibitorprotein interactions, functions of metalloproteins, and enzyme catalysis (Abdel-Azeim, Li, Chung, & Morokuma, 2011;Chen, Liang, Wang, Yi, Zhang, & Zhang, 2014;Duan, Mei, Zhang, Zhang, & Zhang, 2010;Duan, Mei, Zhang, & Zhang, 2009;Fan, Cembran, Ma, & Gao, 2013;Gao, Lu, Duan, Zhang, & Mei, 2011;Hou & Cui, 2013;Hou, McLaughlin, & Wang, 2007;Hu, Zhu, Zhang, Wang, & Zhang, 2010;Hu & Wang,2014;Ke, Wang, Xie, & Zhang, 2009;Keerthana & Kolandaivel, 2014;Meher, Kumar, & Bandyopadhyay, 2014;Smith, Ke, Guo, & Hengge, 2011;Wang et al, 2010Wang et al, , 2013Wang, Wu, Xu, Xie, & Guo, 2011;Wong, Richard, & Gao, 2009;Zhu, He, & Zhang, 2012;Zhu, Xiao et al, 2013). This method can take the polarizable electrostatic effect into account explicitly and accurately treat hydrogen bonding interactions.…”

Section: Introductionmentioning

confidence: 97%

A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation

Chen

Wang

Chen

et al. 2015

Journal of Biomolecular Structure and Dynamics

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Hydrogen bonding and polar interactions play a key role in identification of protein-inhibitor binding specificity. Quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) simulations combined with DFT and semi-empirical Hamiltonian (AM1d, RM1, PM3, and PM6) methods were performed to study the hydrogen bonding and polar interactions of two inhibitors BEN and BEN1 with trypsin. The results show that the accuracy of treating the hydrogen bonding and polar interactions using QM/MM MD simulation of PM6 can reach the one obtained by the DFT QM/MM MD simulation. Quantum mechanics/molecular mechanics generalized Born surface area (QM/MM-GBSA) method was applied to calculate binding affinities of inhibitors to trypsin and the results suggest that the accuracy of binding affinity prediction can be significantly affected by the accurate treatment of the hydrogen bonding and polar interactions. In addition, the calculated results also reveal the binding specificity of trypsin: (1) the amidinium groups of two inhibitors generate favorable salt bridge interaction with Asp189 and form hydrogen bonding interactions with Ser190 and Gly214, (2) the phenyl of inhibitors can produce favorable van der Waals interactions with the residues His58, Cys191, Gln192, Trp211, Gly212, and Cys215. This systematic and comparative study can provide guidance for the choice of QM/MM MD methods and the designs of new potent inhibitors targeting trypsin.

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“…The MM-PB(GB)SA methods have successfully been used to estimate the binding free energy of protein-ligand [30,31] and protein-RNA [32,33] associations. These methods have also been used to study the binding of different inhibitors to protease [34][35][36][37][38][39] and reverse transcriptase (RT) [40]. Recently Worch et al [41] have modeled the interaction propensity of the transmembrane domain (TMD) pairs and computed free energy gain resulting from TMD dimer formation using the MM-PBSA approach.…”

Section: Introductionmentioning

confidence: 98%

Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir

Kar

Knecht

2012

J Comput Aided Mol Des

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Amprenavir (APV) is a high affinity (0.15 nM) HIV-1 protease (PR) inhibitor. However, the affinities of the drug resistant protease variants V32I, I50V, I54V, I54M, I84V and L90M to amprenavir are decreased 3 to 30-fold compared to the wild-type. In this work, the popular molecular mechanics Poisson-Boltzmann surface area method has been used to investigate the effectiveness of amprenavir against the wild-type and these mutated protease variants. Our results reveal that the protonation state of Asp25/Asp25' strongly affects the dynamics, the overall affinity and the interactions of the inhibitor with individual residues. We emphasize that, in contrast to what is often assumed, the protonation state may not be inferred from the affinities but requires pK(a) calculations. At neutral pH, Asp25 and Asp25' are ionized or protonated, respectively, as suggested from pK(a) calculations. This protonation state was thus mainly considered in our study. Mutation induced changes in binding affinities are in agreement with the experimental findings. The decomposition of the binding free energy reveals the mechanisms underlying binding and drug resistance. Drug resistance arises from an increase in the energetic contribution from the van der Waals interactions between APV and PR (V32I, I50V, and I84V mutant) or a rise in the energetic contribution from the electrostatic interactions between the inhibitor and its target (I54M and I54V mutant). For the V32I mutant, also an increased free energy for the polar solvation contributes to the drug resistance. For the L90M mutant, a rise in the van der Waals energy for APV-PR interactions is compensated by a decrease in the polar solvation free energy such that the net binding affinity remains unchanged. Detailed understanding of the molecular forces governing binding and drug resistance might assist in the design of new inhibitors against HIV-1 PR variants that are resistant against current drugs.

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Some insights into mechanism for binding and drug resistance of wild type and I50V V82A and I84V mutations in HIV-1 protease with GRL-98065 inhibitor from molecular dynamic simulations

Cited by 30 publications

References 35 publications

Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance

Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance

A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation

Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir

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