Quantitative evaluation of hydration thermodynamics with a continuum model

Area of Science:

• Computational Chemistry
• Physical Chemistry
• Molecular Modeling

Background:

• Accurate prediction of molecular hydration properties is crucial for understanding chemical and biological processes.
• Continuum models offer a computationally efficient approach to solvation free energy calculations.

Purpose of the Study:

• To quantitatively evaluate a continuum model with classical reaction field formalism for predicting experimental hydration properties (entropies, enthalpies, free energies) of small, uncharged molecules.
• To identify key molecular descriptors and computational factors influencing the accuracy of hydration property predictions.

Main Methods:

• Utilized a continuum solvation model incorporating a classical reaction field.
• Correlated hydration entropies with molecular accessible surface area using five atom types.
• Investigated the impact of solute polarizability, dipole moments, and quadrupole moments on hydration enthalpies.
• Employed density functional theory (DFT) with a DZVPD basis set for dipole moment calculations.

Main Results:

• Achieved satisfactory reproduction of hydration entropies (T delta S) within 1-1.5 kcal/mol for over 40 solutes, primarily based on accessible surface area.
• Reasonable agreement for hydration enthalpies was obtained only when solute polarizability was included.
• Demonstrated strong dependence of electrostatic contributions to hydration enthalpies on dipole moment magnitude and direction.
• DFT calculations accurately predicted experimental dipole moments within 0.1 D.
• Identified significant impact of dipole moment uncertainties (0.1 D) and directional changes (30 degrees) on hydration enthalpy predictions.
• Showed that point charge representations of multipole expansions lead to discrepancies of ~3 kcal/mol in hydration enthalpies.

Conclusions:

• A continuum model, particularly when considering accessible surface area and solute polarizability, can quantitatively rationalize experimental hydration entropies and enthalpies.
• Accurate prediction of molecular dipole moments and their orientation is critical for reliable hydration enthalpy calculations.
• Errors in hydration enthalpy and entropy calculations often compensate, leading to good agreement for free energies of hydration within 1.5 kcal/mol.