Predicting Binding Free Energies: Frontiers and Benchmarks

Mobley, David L.; Gilson, Michael K.

doi:10.1146/annurev-biophys-070816-033654

Cited by 311 publications

(354 citation statements)

References 132 publications

(310 reference statements)

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“…The T4 lysozyme L99A cavity mutant studied here has a buried binding site which readily binds non-polar molecules, making it a common model system for free energy calculations. 68 …”

Section: Theory and Computational Methodsmentioning

confidence: 99%

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo

et al. 2018

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Accurately predicting protein-ligand binding affinities and binding modes is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes. In this technique, the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically-relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.

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“…The T4 lysozyme L99A cavity mutant studied here has a buried binding site which readily binds non-polar molecules, making it a common model system for free energy calculations. 68 …”

Section: Theory and Computational Methodsmentioning

confidence: 99%

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo

et al. 2018

Self Cite

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“…Therefore, a similar active area of research is the prediction of binding affinities for biomolecular complexes from molecular dynamics simulations due to the expected impact such calculations will have in early stage drug discovery. Yet these calculations have a higher level of complexity and are, thus, less mature than those devoted to solvation free energies [29]. Two types of approaches are principally used to compute standard binding free energies using molecular dynamics simulations, namely the alchemical double decoupling method and the potential of mean force method, respectively [30 -33].…”

Section: Introductionmentioning

confidence: 99%

Molecular Simulations of Thermodynamic Properties for the Systemα‐Cyclodextrin/Alcohol in Aqueous Solution

Markthaler

Gebhardt

Jakobtorweihen

et al. 2017

Chemie Ingenieur Technik

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Free-energy calculations based on molecular simulations provide access to a wide range of thermodynamic properties such as the solubility and partitioning of a molecule in and between various phases. It is demonstrated how molecular dynamics free-energy simulations may be used to obtain the solubilities of primary alcohols and n-alkanes in water and binding affinities of primary alcohols to a-cyclodextrin. The equivalence of two distinct routes to calculate binding free energies is shown leading to the conclusion that host-guest binding affinities may be used to probe the underlying molecular force field.

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“…10000, for a similar computational expense) with the low acceptance rate and still see a reasonable number of moves accepted. We believe this relative advantage of standard MC may be a peculiarity of toluene in this particular binding site (which is relatively large compared to the size of toluene, and known to be especially rigid 5,68,94,95 ), and not representative of typical MC performance in condensed phase systems. 44 To further test the relative performance of MC and NCMC, we examined performance of NCMC versus MC move proposals for a larger ligand in the lysozyme binding site, 3-iodotoluene; we find that the presence of the bulky iodo substituent dramatically impairs acceptance of MC moves, presumably due to the larger size of the ligand relative to the size of the binding site (see Section 2.9 for methods).…”

Section: Ncmc Does Not Compare As Favorably To MC For Toluene But Ncmentioning

confidence: 99%

“…The T4 lysozyme L99A cavity mutant studied here has a buried binding site which readily binds non-polar molecules, making it a common model system for free energy calculations. 68 Toluene, a T4 lysozyme L99A binder, was chosen as the initial ligand for testing this method for a number of reasons. One is that toluene's symmetry allows for a convenient check of correctness; symmetric binding modes should have equivalent populations with adequate sampling.…”

Section: We Study a T4 Lysozyme Cavity Mutant Which Binds Simple Ligandsmentioning

confidence: 99%

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

Gill¹,

Lim²,

Grinaway³

et al. 2018

Preprint

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Accurately predicting protein-ligand binding affinities and binding modes is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragmentlike ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes. In this technique, the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically-relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.

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Predicting Binding Free Energies: Frontiers and Benchmarks

Cited by 311 publications

References 132 publications

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo

Molecular Simulations of Thermodynamic Properties for the Systemα‐Cyclodextrin/Alcohol in Aqueous Solution

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

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