Hydration Properties and Solvent Effects for All-Atom Solutes in Polarizable Coarse-Grained Water

Abstract

Due to the importance of water in chemical and biological systems, a coarse-grained representation of the solvent can greatly simplify the description of the system while retaining key thermodynamic properties of the medium. A multiscale solvation model that couples all-atom solutes and polarizable Martini coarse-grained water (AAX/CGS) is developed to reproduce free energies of hydration of organic solutes. Using Monte Carlo/free energy perturbation (MC/FEP) calculations, results from multiscale and all-atom simulations are compared. Improved accuracy is obtained with the AAX/CGS approach for hydrophobic and sulfur- or halogen-containing solutes, but larger deviations are found for polar solute molecules where hydrogen bonding is featured. Furthermore, solvent effects on conformational and tautomeric equilibria of AA solutes were investigated using AA, CG, and GB/SA solvent models. It is found that the CG solvent model can reproduce well the medium effects from experiment and AA simulations; however, the GB/SA solvent model fails in some cases. A 7-30-fold reduction in computational cost is found for the present AAX/CGS multiscale simulations compared to the AA alternative.

Figure 1

Correlation between experimental and computed free energies of hydration (kcal/mol) using 1.14*CM1A (left) and 1.20*CM5 (right) charge models. The results computed with CG and TIP4P water are shown in blue and green, respectively. The dashed red line shows the ideal y = x correlation; the solid lines indicate the best linear least-squares fit of the computed data.

Figure 2

Correlation between experimental and computed free energies of hydration ΔG_hyd (kcal/mol) for the 28 test solutes using 1.14*CM1A (left) and 1.20*CM5 (right) charge models. The results from multiscale and AA simulations are shown in blue and green, respectively. The dashed red line shows the ideal y = x correlation.

Figure 3

Computed probability distributions (a, c, e, g) and free energy profiles (b, d, f, h, i, j) for dihedral angle φ. a,b: 1,2-dichloroethane, φ = Cl-C-C-Cl; c,d: 1,2-dichloropropane, φ = Cl-C-C-Me; e,f: α-dimethoxymethane, φ = C-O-C-O; g, h: β-dimethoxymethane, φ = C-O-C-O; i: (axial)-2-methoxytetrahydropyran, φ = Me-O-C-O; j: (equatorial)-2-methoxytetrahydropyran, φ = Me-O-C-O. S(φ) denotes the probability distribution for the dihedral angle. ΔG(φ) is the cumulative free energy (kcal/mol) relative to G(φ =0°).

Figure 4

Major conformations of (a) 1,2-dichloropropane and (b) 2-methoxytetrahydropyran.

Figure 5

Histogram of the distribution of unsigned errors (kcal/mol) for computed hydration free energies of 70 solute molecules using the polarizable CG and TIP4P water as solvent.