Use of quantum mechanics/molecular mechanics-based FEP method for calculating relative binding affinities of FBPase inhibitors for type-2 diabetes

Rathore, R. S.; Reddy, R. Nageswara; Kondapi, Anand K.; Reddanna, Pallu; Reddy, M. Rami

doi:10.1007/s00214-012-1096-z

Cited by 12 publications

(10 citation statements)

References 38 publications

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“…Therefore, such calculations have so far been performed only for small QM regions, treated with a semiempirical QM approach (SQM). [17][18][19][20] There has been growing interest in employing the reference-potential approach, developed by Gao, Warshel and co-workers. 21,22 In this approach, the relative binding affinity is first calculated at a low-level of theory, typically MM.…”

Section: Introductionmentioning

confidence: 99%

Host–Guest Relative Binding Affinities at Density-Functional Theory Level from Semiempirical Molecular Dynamics Simulations

Wang

Ryde

2019

J. Chem. Theory Comput.

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Relative free energies for the binding of nine cyclic carboxylate ligands to the octaacid deep-cavity host were calculated at the combined density-functional theory and molecular mechanics (DFT/MM) level of theory. The DFT calculations employed the BLYP functional and the 6-31G* basis set for the ligand. We employed free-energy perturbations (FEP) with the reference-potential approach and used molecular dynamics (MD) simulations with the semiempirical quantum mechanical (SQM) PM6-DH+ method for the ligand as an intermediate level between MM and DFT/MM to improve the convergence. Thus, the relative binding free energy of two ligands was first calculated at the MM level by an alchemical transformation from one ligand to another in both the bound and unbound states. Then, for each ligand the free-energy correction for going from the MM to the SQM/MM potentials was calculated using explicit SQM/MM MD simulations. Finally, the free-energy correction for going from the SQM/MM to the DFT/MM potentials was estimated with FEP without running any DFT/MM simulations. Instead, the free energy was calculated by single-step exponential averaging (ssEA) or employing the cumulant approximation to the second order (CA). The results show that CA converges much better than ssEA and with 500-4500 DFT/MM single-point energy calculations, converged free energies with a precision of 0.3 kJ/mol can be obtained. These free energies reproduce the experimental binding free energy differences with a mean absolute deviation of 3.4 kJ/mol, a correlation (R 2) of 0.97 and correct signs for all of the eight free-energy differences. This is appreciably better than the results obtained at the SQM/MM level of theory and also slightly better than those obtained with MM. We show that the convergence of the SQM/MM→DFT/MM perturbations can be monitored by the use of Wu and Kofke's bias metric Π and by the standard deviation of the difference between the SQM/MM and DFT/MM energies. Finally, we show that the use of the intermediate SQM/MM MD simulations improves the convergence of the free energies by a factor of at least two, compared to doing direct MM→DFT/MM perturbations.

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Section: Introductionmentioning

confidence: 99%

Host–Guest Relative Binding Affinities at Density-Functional Theory Level from Semiempirical Molecular Dynamics Simulations

Wang

Ryde

2019

J. Chem. Theory Comput.

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“…One approach is to use QM for only a small, but interesting, part of the system (e.g., the ligand) and MM for the remainder, the QM/MM approach. A few full FES ligand‐binding studies have been published with such a partitioning, treating only the ligand by QM and using SQM calculations …”

Section: Introductionmentioning

confidence: 99%

Converging ligand‐binding free energies obtained with free‐energy perturbations at the quantum mechanical level

2016

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In this article, the convergence of quantum mechanical (QM) free‐energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa‐acid deep‐cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158–224 atoms). We use single‐step exponential averaging (ssEA) and the non‐Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi‐empirical PM6‐DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free‐energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

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“…Only a few of the previous QM studies of ligand binding have used an AP approach, despite that this is the gold standard in binding free‐energy calculations at the MM level. Most other studies used either geometries from docking, QM/MM‐optimized geometries, average structures from MD, or a limited ensemble of structures from MD .…”

Section: Introductionmentioning

confidence: 99%

Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model

2015

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The most general way to improve the accuracy of binding-affinity calculations for protein-ligand systems is to use quantum-mechanical (QM) methods together with rigorous alchemical-perturbation (AP) methods. We explore this approach by calculating the relative binding free energy of two synthetic disaccharides binding to galectin-3 at a reasonably high QM level (dispersion-corrected density functional theory with a triple-zeta basis set) and with a sufficiently large QM system to include all short-range interactions with the ligand (744-748 atoms). The rest of the protein is treated as a collection of atomic multipoles (up to quadrupoles) and polarizabilities. Several methods for evaluating the binding free energy from the 3600 QM calculations are investigated in terms of stability and accuracy. In particular, methods using QM calculations only at the endpoints of the transformation are compared with the recently proposed non-Boltzmann Bennett acceptance ratio (NBB) method that uses QM calculations at several stages of the transformation. Unfortunately, none of the rigorous approaches give sufficient statistical precision. However, a novel approximate method, involving the direct use of QM energies in the Bennett acceptance ratio method, gives similar results as NBB but with better precision, ∼3 kJ/mol. The statistical error can be further reduced by performing a greater number of QM calculations.

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Use of quantum mechanics/molecular mechanics-based FEP method for calculating relative binding affinities of FBPase inhibitors for type-2 diabetes

Cited by 12 publications

References 38 publications

Host–Guest Relative Binding Affinities at Density-Functional Theory Level from Semiempirical Molecular Dynamics Simulations

Host–Guest Relative Binding Affinities at Density-Functional Theory Level from Semiempirical Molecular Dynamics Simulations

Converging ligand‐binding free energies obtained with free‐energy perturbations at the quantum mechanical level

Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model

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