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The Excess Chemical Potential of Water at the Interface with a Protein from End Point Simulations.

ABSTRACT: We use end point simulations to estimate the excess chemical potential of water in the homogeneous liquid and at the interface with a protein in solution. When the pure liquid is taken as the reference, the excess chemical potential of interfacial water is the difference between the solvation free energy of a water molecule at the interface and in the bulk. Using the homogeneous liquid as an example, we show that the solvation free energy for growing a water molecule can be estimated by applying UWHAM to the simulation data generated from the initial and final states (i.e., "the end points") instead of multistate free energy perturbation simulations because of the possible overlaps of the configurations sampled at the end points. Then end point simulations are used to estimate the solvation free energy of water at the interface with a protein in solution. The estimate of the solvation free energy at the interface from two simulations at the end points agrees with the benchmark using 32 states within a 95% confidence interval for most interfacial locations. The ability to accurately estimate the excess chemical potential of water from end point simulations facilitates the statistical thermodynamic analysis of diverse interfacial phenomena. Our focus is on analyzing the excess chemical potential of water at protein receptor binding sites with the goal of using this information to assist in the design of tight binding ligands.

SUBMITTER: Zhang BW

PROVIDER: S-EPMC5939383 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The Excess Chemical Potential of Water at the Interface with a Protein from End Point Simulations.

Zhang Bin W BW Cui Di D Matubayasi Nobuyuki N Levy Ronald M RM

The journal of physical chemistry. B 20180423 17

We use end point simulations to estimate the excess chemical potential of water in the homogeneous liquid and at the interface with a protein in solution. When the pure liquid is taken as the reference, the excess chemical potential of interfacial water is the difference between the solvation free energy of a water molecule at the interface and in the bulk. Using the homogeneous liquid as an example, we show that the solvation free energy for growing a water molecule can be estimated by applying ...[more]

PMID: 29634902

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Project description:End-point free energy calculations using MM-GBSA and MM-PBSA provide a detailed understanding of molecular recognition in protein-ligand interactions. The binding free energy can be used to rank-order protein-ligand structures in virtual screening for compound or target identification. Here, we carry out free energy calculations for a diverse set of 11 proteins bound to 14 small molecules using extensive explicit-solvent MD simulations. The structure of these complexes was previously solved by crystallography and their binding studied with isothermal titration calorimetry (ITC) data enabling direct comparison to the MM-GBSA and MM-PBSA calculations. Four MM-GBSA and three MM-PBSA calculations reproduced the ITC free energy within 1 kcal·mol(-1) highlighting the challenges in reproducing the absolute free energy from end-point free energy calculations. MM-GBSA exhibited better rank-ordering with a Spearman ? of 0.68 compared to 0.40 for MM-PBSA with dielectric constant (? = 1). An increase in ? resulted in significantly better rank-ordering for MM-PBSA (? = 0.91 for ? = 10), but larger ? significantly reduced the contributions of electrostatics, suggesting that the improvement is due to the nonpolar and entropy components, rather than a better representation of the electrostatics. The SVRKB scoring function applied to MD snapshots resulted in excellent rank-ordering (? = 0.81). Calculations of the configurational entropy using normal-mode analysis led to free energies that correlated significantly better to the ITC free energy than the MD-based quasi-harmonic approach, but the computed entropies showed no correlation with the ITC entropy. When the adaptation energy is taken into consideration by running separate simulations for complex, apo, and ligand (MM-PBSAADAPT), there is less agreement with the ITC data for the individual free energies, but remarkably good rank-ordering is observed (? = 0.89). Interestingly, filtering MD snapshots by prescoring protein-ligand complexes with a machine learning-based approach (SVMSP) resulted in a significant improvement in the MM-PBSA results (? = 1) from ? = 0.40 to ? = 0.81. Finally, the nonpolar components of MM-GBSA and MM-PBSA, but not the electrostatic components, showed strong correlation to the ITC free energy; the computed entropies did not correlate with the ITC entropy.

Project description:We present molecular dynamics simulations of the liquid-vapor interface of 1M salt solutions of nonpolarizable NaCl, NaBr, and NaI in polarizable transferable intermolecular potential 4-point with charge dependent polarizability water [B. A. Bauer et al., J. Chem. Theory Comput. 5, 359 (2009)]; this water model accommodates increased solvent polarizability (relative to the condensed phase) in the interfacial and vapor regions. We employ fixed-charge ion models developed in conjunction with the TIP4P-QDP water model to reproduce ab initio ion-water binding energies and ion-water distances for isolated ion-water pairs. The transferability of these ion models to the condensed phase was validated with hydration free energies computed using thermodynamic integration (TI) and appropriate energy corrections. Density profiles of Cl(-), Br(-), and I(-) exhibit charge layering in the interfacial region; anions and cation interfacial probabilities show marked localization, with the anions penetrating further toward the vapor than the cations. Importantly, in none of the cases studied do anions favor the outermost regions of the interface; there is always an aqueous region between the anions and vapor phase. Observed interfacial charge layering is independent of the strength of anion-cation interactions as manifest in anion-cation contact ion pair peaks and solvent separated ion pair peaks; by artificially modulating the strength of anion-cation interactions (independent of their interactions with solvent), we find little dependence on charge layering particularly for the larger iodide anion. The present results reiterate the widely held view of the importance of solvent and ion polarizability in mediating specific anion surface segregation effects. Moreover, due to the higher parametrized polarizability of the TIP4P-QDP condensed phase {1.31 A(3) for TIP4P-QDP versus 1.1 A(3) (TIP4P-FQ) and 0.87 A(3) (POL3) [Ponder and Case, Adv. Protein Chem. 66, 27 (2003)]} based on ab initio calculations of the condensed-phase polarizability reduction in liquid water, the present simulations highlight the role of water polarizability in inducing water molecular dipole moments parallel to the interface normal (and within the interfacial region) so as to favorably oppose the macrodipole generated by the separation of anion and cation charge. Since the TIP4P-QDP water polarizability approaches that of the experimental vapor phase value for water, the present results suggest a fundamental role of solvent polarizability in accommodating the large spatial dipole generated by the separation of ion charges. The present results draw further attention to the question of what exact value of condensed phase water polarizability to incorporate in classical polarizable water force fields.

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The Excess Chemical Potential of Water at the Interface with a Protein from End Point Simulations.

Publications

The Excess Chemical Potential of Water at the Interface with a Protein from End Point Simulations.

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