Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model

Wang, Wei; Kollman, Peter A.

doi:10.1006/jmbi.2000.4057

Cited by 302 publications

(267 citation statements)

References 41 publications

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“…19 The calculations of Paulsen and Ornstein show that R ≈ 0.5 and ≈1.043 are the best values to use to correlate the calculated binding free energies with the respective experimental values. 20 In Wang's work, R ≈ 0.5 and ≈ 1.0 can give the best predicted binding affinities to a group of avidin ligands using the AMBER force field. 21 Jones-Herzog and Jorgensen observed that the addition of another term concerned with molecular solvent-accessible surfaces as well as R ) 0.131 and ) 0.131 could produce the best correlation.…”

Section: Mm/pbsa Modelsmentioning

confidence: 97%

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Predictions of Binding of a Diverse Set of Ligands to Gelatinase-A by a Combination of Molecular Dynamics and Continuum Solvent Models

Hou

Guo

2002

J. Phys. Chem. B

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The free energies of binding, ∆G bind , between a diverse set of eight hydroxamate inhibitors with gelatinase-A (MMP-2) were computed by using the recently developed MM/PBSA approach. In this paper, a nonbonded model was used to represent the potentials of the catalytic zinc center. Molecular dynamics (MD) simulations were used to generate the thermally averaged ensemble of conformations of the ligand-protein complexes. On the basis of the trajectories from MD simulations, the free energies of binding were calculated using molecular mechanics, the continuum solvent model, surface area estimation, and normal-mode analysis. The results show that MM/PBSA not only can rank the studied ligands effectively but also can reproduce the experimental binding free energies successfully. The predicted binding free energies correlate well with the experimental values (r ) 0.84, q ) 0.78). As a comparison, the free energies of binding were also computed by using the linear interaction energy approximation (LIE). The overall agreement between the calculated and experimental values for the diverse set of ligands means that the MM/PBSA approach is a useful tool for the general evaluation of protein-ligand interactions. The analysis of the separate energy terms contributing to MM/PBSA free energy indicates that the association between hydroxamate and MMP-2 is mainly driven by more favorable van der Waals/nonpolar interactions in the complex than in solution.

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Section: Mm/pbsa Modelsmentioning

confidence: 97%

“…[15][16][17][18][19][20][21][22] In the LIE approach proposed by Åqvist, ∆G b can be computed from ligand interaction energies in the bound and free states. On the basis of the linear response consideration, only averages of the interaction energies between the ligand and its surroundings need to be evaluated.…”

Section: Introductionmentioning

confidence: 99%

Predictions of Binding of a Diverse Set of Ligands to Gelatinase-A by a Combination of Molecular Dynamics and Continuum Solvent Models

Hou

Guo

2002

J. Phys. Chem. B

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“…Wang et al recently studied HIV protease dimerization using MM-PBSA [76]. They firstly calculated the binding free energies between the wild-type HIV protease with the two catalytic aspartic acid residues at different protonation states.…”

Section: Protein-protein Protein-peptide Interactionsmentioning

confidence: 99%

“…As to for what systems MM-PBSA/GBSA tend to work well and for what systems not, in general, for systems that have substantial contributions to the free energy from buried charges, MM-PBSA/GBSA may not perform well; on the other hand, good results can be expected for the hydrophobic interaction dominated systems. Yet, this is not always the case and good results of both relative and absolute free energies could be observed for almost all kinds of systems, including proteins [14,44], nucleic acids [50][51], protein-ligand [13,54,63], and protein-protein [76][77][78][79]. It is emphasized that the above summary may be biased to some degree since we only selected some representative papers published recently in this field.…”

Section: E Summarymentioning

confidence: 99%

Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models

Wang¹,

Hou²,

2006

CAD

332

262

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Abstract:Recently, the combination of state-of-the-art molecular mechanical force fields with continuum solvation models enables us to make relatively accurate predictions of both structures and free energies for macromolecules from molecular dynamics trajectories. The first part of this review is focused on the history and basic theory of free energy calculations based on physically effective energy functions. The second part illustrates the applications of free energy calculations on many biological systems, including proteins, DNA, RNA, protein-ligand, protein-protein, protein-nucleic acid complexes, etc. Finally, the prospective and possible strategies to improve the techniques of MM-PBSA and MM-GBSA is discussed.

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“…The binding free energies were computed using the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method [10,11]. In addition, we present an optimized protocol using the Autodock program based on cross-docking of the five inhibitors to the binding site.…”

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confidence: 99%

Insight into ligand selectivity in HCV NS5B polymerase: molecular dynamics simulations, free energy decomposition and docking

Froeyen

Herdewijn

2009

J Mol Model

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Modeling studies were performed on HCV NS5B Polymerase in an effort to design new inhibitors. The binding models of five different scaffold inhibitors were investigated and compared by using molecular dynamics simulations, free energy calculation and decomposition. Our results show Tyr448 plays the most critical role in the binding of most inhibitors. In addition, favorable contributions of residues Pro197, Arg200, Cys366, Met414 and Tyr448 in a deep hydrophobic pocket prove to be important for the selectivity of inhibitors. Furthermore, an optimized docking protocol was presented based on cross-docking the five inhibitors in the palm binding site of this enzyme using the Autodock program. This protocol was used later to virtually screen NCI and Maybridge diversity set libraries. The binding site was profiled via the statistics and analysis of the hydrogen bond networks formed between the receptor and the top-ranked diversity set compounds. Based on our detailed binding site analysis two useful rules were proposed to guide the selection of promising hits.Response to Reviewers: Question1: It is a pity that nothing in detail is discussed about found structures resulting from the virtual screening. Did the authors find new promising ligands with high (higher than the template ligands?) affinity and are they structurally diverse or similar to the used ones?Answer: We have found some promising compounds after the virtual screening. They are structurally diverse. Most of them form hydrogen bonds with the critical residues such as Tyr448 and have strong hydrophobic interaction with the residues in the deep hydrophobic pocket mentioned in our article. These compounds are under biological test.Question2: Additionally to figure 5 at least one figure should be added, showing the amino acid residues of the active site with the discussed most important interactions with one (the best?) ligand. This would considerably help to understand the discussion without looking in the original pdb-files. AbstractModeling studies were performed on HCV NS5B Polymerase in an effort to design new inhibitors. The binding models of five different scaffold inhibitors were investigated and compared by using molecular dynamics simulations, free energy calculation and decomposition. Our results show Tyr448 plays the most critical role in the binding of most inhibitors. In addition, favorable contributions of residues Pro197, Arg200, Cys366, Met414 and Tyr448 in a deep hydrophobic pocket prove to be important for the selectivity of inhibitors.Furthermore, an optimized docking protocol was presented based on cross-docking the five inhibitors in the palm binding site of this enzyme using the Autodock program. This protocol was used later to virtually screen NCI and Maybridge diversity set libraries. The binding site was profiled via the statistics and analysis of the hydrogen bond networks formed between the receptor and the top-ranked diversity set compounds. Based on our detailed binding site analysis two useful rules were proposed to ...

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Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model

Cited by 302 publications

References 41 publications

Predictions of Binding of a Diverse Set of Ligands to Gelatinase-A by a Combination of Molecular Dynamics and Continuum Solvent Models

Predictions of Binding of a Diverse Set of Ligands to Gelatinase-A by a Combination of Molecular Dynamics and Continuum Solvent Models

Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models

Insight into ligand selectivity in HCV NS5B polymerase: molecular dynamics simulations, free energy decomposition and docking

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