The electrostatic response of water to neutral polar solutes: Implications for continuum solvent modeling

Muddana, Hari S.; Sapra, Neil V.; Fenley, Andrew T.; Gilson, Michael K.

doi:10.1063/1.4808376

Cited by 20 publications

(17 citation statements)

References 86 publications

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“…Previous studies have shown that explicit water effects might play an important role in binding for the CB7 system [20, 21, 47, 48], and suggested that expulsion of thermodynamically disfavored structured waters in the host’s cavity might drive the high binding affinities of some guests for CB7. Nonetheless, the overall performance has been similar for both continuum and explicit-water solvation models, and some of the better performing methods here used continuum solvation models.…”

Section: Discussionmentioning

confidence: 99%

The SAMPL4 host–guest blind prediction challenge: an overview

Muddana

Fenley

Mobley

et al. 2014

J Comput Aided Mol Des

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199

266

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Prospective validation of methods for computing binding affinities can help assess their predictive power and thus set reasonable expectations for their performance in drug design applications. Supramolecular host–guest systems are excellent model systems for testing such affinity prediction methods, because their small size and limited conformational flexibility, relative to proteins, allows higher throughput and better numerical convergence. The SAMPL4 prediction challenge therefore included a series of host–guest systems, based on two hosts, cucurbit[7]uril and octa-acid. Binding affinities in aqueous solution were measured experimentally for a total of 23 guest molecules. Participants submitted 35 sets of computational predictions for these host–guest systems, based on methods ranging from simple docking, to extensive free energy simulations, to quantum mechanical calculations. Over half of the predictions provided better correlations with experiment than two simple null models, but most methods underperformed the null models in terms of root mean squared error and linear regression slope. Interestingly, the overall performance across all SAMPL4 submissions was similar to that for the prior SAMPL3 host–guest challenge, although the experimentalists took steps to simplify the current challenge. While some methods performed fairly consistently across both hosts, no single approach emerged as consistent top performer, and the nonsystematic nature of the various submissions made it impossible to draw definitive conclusions regarding the best choices of energy models or sampling algorithms. Salt effects emerged as an issue in the calculation of absolute binding affinities of cucurbit[7]uril-guest systems, but were not expected to affect the relative affinities significantly. Useful directions for future rounds of the challenge might involve encouraging participants to carry out some calculations that replicate each others’ studies, and to systematically explore parameter options.

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Section: Discussionmentioning

confidence: 99%

The SAMPL4 host–guest blind prediction challenge: an overview

Muddana

Fenley

Mobley

et al. 2014

J Comput Aided Mol Des

Self Cite

199

266

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“…Hydration free energies were computed through stepwise decoupling of the solute from the solvent [42]. The decoupling was carried out in two main stages: first, the electrostatic interactions between solute and water were decoupled in 10 steps with coupling parameter values of λ = [0.00, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1.00].…”

Section: Methodsmentioning

confidence: 99%

The SAMPL4 hydration challenge: evaluation of partial charge sets with explicit-water molecular dynamics simulations

Muddana

Sapra

Fenley

et al. 2014

J Comput Aided Mol Des

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We used blind predictions of the 47 hydration free energies in the SAMPL4 challenge to test multiple partial charges models in the context of explicit solvent free energy simulations with the GAFF force field. One of the partial charge models, IPolQ-Mod, is a fast continuum solvent-based implementation of the IPolQ approach. The AM1-BCC, RESP and IpolQ-Mod approaches all perform reasonably well (R2 > 0.8), while Vcharge, though faster, gives less accurate results (R2 of 0.5). The AM1-BCC results are more accurate than those of RESP for tertiary amines and nitrates, but the overall difference in accuracy between these methods is not statistically significant. Interestingly, the IPolQ-Mod method is found to yield partial charges in very close agreement with RESP. This observation suggests that the success of RESP may be attributed to its fortuitously approximating the arguably more rigorous IPolQ approach.

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“…A hierarchy of approximations, many of which are essentially unavoidable, separates the PB (and the GB) from the more fundamental explicit solvent representation, and from reality . These approximations result in notable limitations of the pure GB or PB frameworks, such as their inability to account for many prominent explicit solvent effects, including charge hydration asymmetry and other water multipole effects, water ‘bridges,’ electrostriction and dielectric saturation . Also, accurate estimates of total solvation energies, and especially their differences in conformational transitions, need accurate nonpolar estimates of the nonpolar contribution .…”

Section: Implicit Solvent Modelsmentioning

confidence: 99%

Water models for biomolecular simulations

Onufriev

Izadi²

2017

WIREs Comput Mol Sci

176

225

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Modern simulation and modeling approaches to investigation of biomolecular structure and function rely heavily on a variety of methods—water models—to approximate the influence of solvent. We give a brief overview of several distinct classes of available water models, with the emphasis on the conceptual basis at each level of approximation. The main focus is on classes of models most widely used in atomistic simulations, including popular implicit and explicit solvent models. Among the latter, nonpolarizable N‐point models are covered in most detail, including some recent methodological advances and nuances. Notes on practical availability and usage in biomolecular simulations are included. Atomistic simulations that were hardly possible only a short while ago have revealed significant problems that can be traced to deficiencies of most commonly used N‐point water models. Recently developed models of this class approximate experimental properties of liquid water much closer than before, and show promise in practical biomolecular simulations. Obstacles to wider adoption of these more accurate water models, both technical and conceptual, are discussed. It is argued that verifying robustness of simulation results to the choice of water model can be of immediate benefit even in the absence of a clear replacement for older models; a specific strategy is proposed. The review is concluded with a discussion on how force‐field development efforts can benefit from better solvent models, and vice versa. WIREs Comput Mol Sci 2018, 8:e1347. doi: 10.1002/wcms.1347 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods

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The electrostatic response of water to neutral polar solutes: Implications for continuum solvent modeling

Cited by 20 publications

References 86 publications

The SAMPL4 host–guest blind prediction challenge: an overview

The SAMPL4 host–guest blind prediction challenge: an overview

The SAMPL4 hydration challenge: evaluation of partial charge sets with explicit-water molecular dynamics simulations

Water models for biomolecular simulations

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