Simplified classical water models are currently an indispensable component in practical atomistic simulations. Yet, despite several decades of intense research, these models are still far from perfect. Presented here is an alternative approach to constructing widely used point charge water models. In contrast to the conventional approach, we do not impose any geometry constraints on the model other than the symmetry. Instead, we optimize the distribution of point charges to best describe the “electrostatics” of the water molecule. The resulting “optimal” 3-charge, 4-point rigid water model (OPC) reproduces a comprehensive set of bulk properties significantly more accurately than commonly used rigid models: average error relative to experiment is 0.76%. Close agreement with experiment holds over a wide range of temperatures. The improvements in the proposed model extend beyond bulk properties: compared to common rigid models, predicted hydration free energies of small molecules using OPC are uniformly closer to experiment, with root-mean-square error <1 kcal/mol.

Classical 3-point rigid water models are most widely used due to their computational efficiency. Recently, we introduced a new approach to constructing classical rigid water models [S. Izadi et al., J. Phys. Chem. Lett. 5, 3863 (2014)], which permits a virtually exhaustive search for globally optimal model parameters in the sub-space that is most relevant to the electrostatic properties of the water molecule in liquid phase. Here we apply the approach to develop a 3-point Optimal Point Charge (OPC3) water model. OPC3 is significantly more accurate than the commonly used water models of same class (TIP3P and SPCE) in reproducing a comprehensive set of liquid bulk properties, over a wide range of temperatures. Beyond bulk properties, we show that OPC3 predicts the intrinsic charge hydration asymmetry (CHA) of water - a characteristic dependence of hydration free energy on the sign of the solute charge - in very close agreement with experiment. Two other recent 3-point rigid water models, TIP3PFB and H2ODC, each developed by its own, completely different optimization method, approach the global accuracy optimum represented by OPC3 in both the parameter space and accuracy of bulk properties. Thus, we argue that an accuracy limit of practical 3-point rigid non-polarizable models has effectively been reached; remaining accuracy issues are discussed.

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

Unconstrained atomistic simulations of intrinsically disordered proteins and peptides (IDP) remain a challenge: widely used, “general purpose” water models tend to favor overly compact structures relative to experiment. Here we have performed a total of 93 μs of unrestrained MD simulations to explore, in the context of IDPs, a recently developed “general-purpose” 4-point rigid water model OPC, which describes liquid state of water close to experiment. We demonstrate that OPC, together with a popular AMBER force field ff99SB, offers a noticeable improvement over TIP3P in producing more realistic structural ensembles of three common IDPs benchmarks: 55-residue apo N-terminal zinc-binding domain of HIV-1 integrase (“protein IN”), amyloid β-peptide (Aβ42) (residues 1-42), and 26-reside H4 histone tail. As a negative control, computed folding profile of a regular globular miniprotein (CLN025) in OPC water is in appreciably better agreement with experiment than that obtained in TIP3P, which tends to overstabilize the compact native state relative to the extended conformations. We employed Aβ42 peptide to investigate the possible influence of the solvent box size on simulation outcomes. We advocate a cautious approach for simulations of IDPs: we suggest that the solvent box size should be at least four times the radius of gyration of the random coil corresponding to the IDP. The computed free energy landscape of protein IN in OPC resembles a shallow “tub” – conformations with substantially different degrees of compactness that are within 2 k B T of each other. Conformations with very different secondary structure content coexist within 1 k B T of the global free energy minimum. States with higher free energy tend to have less secondary structure. Computed low helical content of the protein has virtually no correlation with its degree of compactness, which calls into question the possibility of using the helicity as a metric for assessing performance of water models for IDPs, when the helicity is low. Predicted radius of gyration ( R g ) of H4 histone tail in OPC water falls in-between that of a typical globular protein and a fully denatured protein of the same size; the predicted R g is consistent with two independent predictions. In contrast, H4 tail in TIP3P water is as compact as the corresponding globular protein. The computed free energy landscape of H4 tail in OPC is relatively flat over a significant range of compactness, which, we argue, is consistent with its biological function as facilitator of internucleosome interactions.

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