Solvation free energies<i>via</i>alchemical simulations: let's get honest about sampling, once more

Procacci, Piero

doi:10.1039/c9cp02808k

Cited by 23 publications

(22 citation statements)

References 59 publications

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“…The Metropolis acceptance criterion ensures that simulations in all states still converge towards the equilibrium distribution. 32 As mentioned in the introduction, all λ windows need to be simulated at equilibrium in EQ calculations, and some of these can require sampling unphysical states which might have even slower correlation times than the physical states, [34][35][36] necessitating very long sampling times despite the use of enhanced sampling techniques. 2.3.…”

Section: 2mentioning

confidence: 99%

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Challenges Encountered Applying Equilibrium and Nonequilibrium Binding Free Energy Calculations

et al. 2021

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Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. However, among other issues, inadequate sampling can reduce accuracy, limiting the value of the technique.In this paper we apply absolute binding free energy calculations to ligands binding to T4 lysozyme L99A and HSP90 using equilibrium and non-equilibrium approaches. We highlight sampling problems encountered in these systems, such as slow side chain rearrangements and slow changes of water placement upon ligand binding. These same types of challenges are likely to show up in other protein-ligand systems as well and we propose some strategies to diagnose and test for such problems in alchemical free energy calculations. We also explore similarities and differences in how the equilibrium and the non-equilibrium approaches handle these problems. Our results show the large amount of work still to be done to make free energy calculations robust and reliable and provide insight for future research in this area. File list (2)download file view on ChemRxiv NEQ_binding.pdf (30.14 MiB) download file view on ChemRxiv SI.pdf (8.25 MiB)

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Section: 2mentioning

confidence: 99%

“…Complete settings can be found in the mdp files provided in the SI. Although the convergence rate can be different among λ windows, [34][35][36] we ran all alchemical states for an equal amount of time for convenience. The overall convergence of the free energy difference will therefore be determined by the slowest converging window.…”

Section: 2mentioning

confidence: 99%

Challenges Encountered Applying Equilibrium and Nonequilibrium Binding Free Energy Calculations

et al. 2021

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“…(18), and Eqs. (14), (15), and (16), that the λ -functions with both of the soft-core functions we are considering diverges to +∞ at u sc = u max where the first derivative of the soft-core function is zero. Interestingly, the characteristics of the singularity are system-independent (the term λ 0 (u)u (u sc ) is zero at the singularity) and they depend only on the nature of the soft-core function.…”

Section: Soft-core Binding Energy Functions To Reduce Order/disordmentioning

confidence: 92%

“…Both forms of f sc (y) above are invertible and lead to a C(2)-smooth soft-core binding energy function suitable for molecular dynamics applications when included in Eq. (14). The soft-core binding energy function of Eqs.…”

Section: Soft-core Binding Energy Functions To Reduce Order/disordmentioning

confidence: 99%

“…1,2 Molecular simulations of molecular binding are limited by the incomplete description of the chemical system, [3][4][5][6] by the quality of energy functions 7-10 as well as, and probably to a less understood extent, by insufficient conformational sampling. [11][12][13][14] One of the primary applications of computational models of molecular binding is to provide an estimate of the standard free energy of binding, ∆G • b , or, equivalently, the equilibrium constant, K b , for the association equilibrium R + L RL, between two molecules R and L. For example, the binding of a drug molecule to a protein receptor. 15 While many strategies have been proposed, [16][17][18][19] alchemical relative binding free energy methods 20 are emerging as the leading approaches in pharmaceuticals applications.…”

Section: Introductionmentioning

confidence: 99%

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Perturbation potentials to overcome order/disorder transitions in alchemical binding free energy calculations

Pal

Gallicchio

2019

The Journal of Chemical Physics

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We investigate the role of order/disorder transitions in alchemical simulations of protein-ligand absolute binding free energies. We show, in the context of a potential of mean force description, that for a benchmarking system (the complex between the L99A mutant of T4 lysozyme and 3-iodotoluene) and for a more challenging system relevant for medicinal applications (the complex of the farnesoid X receptor and inhibitor 26 from a recent D3R challenge) that order/disorder transitions can significantly hamper Hamiltonian replica exchange sampling efficiency and slow down the rate of equilibration of binding free energy estimates. We further show that our analytical model of alchemical binding combined with the formalism developed by Straub et al. for the treatment of order/disorder transitions of molecular systems can be successfully employed to analyze the transitions and help design alchemical schedules and soft-core functions that avoid or reduce the adverse effects of rare binding/unbinding transitions. The results of this work pave the way for the application of these techniques to the alchemical estimation with explicit solvation of hydration free energies and absolute binding free energies of systems undergoing order/disorder transitions.

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Development and test of highly accurate endpoint free energy methods. 1: Evaluation of ABCG2 charge model on solvation free energy prediction and optimization of atom radii suitable for more accurate solvation free energy prediction by the PBSA method

Sun

Hou

et al. 2023

J Comput Chem

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Accurate estimation of solvation free energy (SFE) lays the foundation for accurate prediction of binding free energy. The Poisson‐Boltzmann (PB) or generalized Born (GB) combined with surface area (SA) continuum solvation method (PBSA and GBSA) have been widely used in SFE calculations because they can achieve good balance between accuracy and efficiency. However, the accuracy of these methods can be affected by several factors such as the charge models, polar and nonpolar SFE calculation methods and the atom radii used in the calculation. In this work, the performance of the ABCG2 (AM1‐BCC‐GAFF2) charge model as well as other two charge models, that is, RESP (Restrained Electrostatic Potential) and AM1‐BCC (Austin Model 1‐bond charge corrections), on the SFE prediction of 544 small molecules in water by PBSA/GBSA was evaluated. In order to improve the performance of the PBSA prediction based on the ABCG2 charge, we further explored the influence of atom radii on the prediction accuracy and yielded a set of atom radius parameters for more accurate SFE prediction using PBSA based on the ABCG2/GAFF2 by reproducing the thermodynamic integration (TI) calculation results. The PB radius parameters of carbon, oxygen, sulfur, phosphorus, chloride, bromide and iodine, were adjusted. New atom types, on, oi, hn1, hn2, hn3, were introduced to further improve the fitting performance. Then, we tuned the parameters in the nonpolar SFE model using the experimental SFE data and the PB calculation results. By adopting the new radius parameters and new nonpolar SFE model, the root mean square error (RMSE) of the SFE calculation for the 544 molecules decreased from 2.38 to 1.05 kcal/mol. Finally, the new radius parameters were applied in the prediction of protein‐ligand binding free energies using the MM‐PBSA method. For the eight systems tested, we could observe higher correlation between the experiment data and calculation results and smaller prediction errors for the absolute binding free energies, demonstrating that our new radius parameters can improve the free energy calculation using the MM‐PBSA method.

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Solvation free energiesviaalchemical simulations: let's get honest about sampling, once more

Abstract: Free energy perturbation (FEP) approaches with stratification have seen widespread and increasing use in computational studies of biologically relevant molecules.

Cited by 23 publications

References 59 publications

Challenges Encountered Applying Equilibrium and Nonequilibrium Binding Free Energy Calculations

Challenges Encountered Applying Equilibrium and Nonequilibrium Binding Free Energy Calculations

Perturbation potentials to overcome order/disorder transitions in alchemical binding free energy calculations

Development and test of highly accurate endpoint free energy methods. 1: Evaluation of ABCG2 charge model on solvation free energy prediction and optimization of atom radii suitable for more accurate solvation free energy prediction by the PBSA method

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