Multipole electrostatics in hydration free energy calculations.

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Physical Chemistry

Background:

• Hydration free energy (HFE) is vital for predicting molecular solubility in pharmaceutical and chemical processes.
• Accurate HFE prediction is a key benchmark for molecular mechanics force fields.

Purpose of the Study:

• To systematically investigate hydration free energy calculations using the AMOEBA polarizable force field under diverse conditions.
• To compare different methods for deriving atomic multipoles and evaluate the impact of basis sets on HFE accuracy.

Main Methods:

• Alchemical free energy calculations using the Bennett Acceptance Ratio method for seven small organic molecules.
• Derivation of atomic multipoles using two approaches: distributed multipole analysis and fitting to the electrostatic potential.
• Utilizing MP2 level wave functions with four basis sets (6-311G*, 6-311++G(2d,2p), cc-pVTZ, aug-cc-pVTZ) for multipole derivation.

Main Results:

• HFEs calculated with all four basis sets showed good agreement with experimental data, with a root mean square error of 0.63 kcal/mol for the aug-cc-pVTZ basis set.
• The aug-cc-pVTZ basis set demonstrated the best performance, while 6-311++G(2d,2p) offered comparable accuracy and better efficiency for larger systems.
• Inclusion of diffuse basis functions is important for accurate intermolecular interactions, and long-range corrections for van der Waals interactions have a minor but systematic effect.

Conclusions:

• The AMOEBA polarizable force field, particularly with the aug-cc-pVTZ basis set, provides accurate hydration free energies.
• Basis set choice significantly impacts HFE accuracy, with diffuse functions being crucial.
• Further investigations into hybrid approaches combining polarizable solutes with fixed-charge water are warranted.