Solvation free energy (SFE) is a basic concept used in many areas. The accurate prediction of SFE lays the foundation for accurate simulation of biological process, for example, binding of a free ligand to its target receptor. SFE and binding free energy (BFE) calculations using MM/PBSA or MM/GBSA methods are widely used for the good balance between efficiency and accuracy. However, the accuracy of these methods are affected by several factors including the charge models, polar SFE calculation methods, and the nonpolar contributions. In this work, the performance of the newly developed ABCG2 charge model (He et al., J. Chem. Phys. 2020, 153, 114502) as well as other two charge models (RESP and AM1-BCC) on SFE prediction of 441 small molecules in water by MM/PBSA and MM/GBSA was evaluated. For the most promising combination, ABCG2 and MM/PBSA, we further explored the influence of atom radii on the prediction polar HSF and yield a new set of atom radii parameters suitable for more accurate SFE prediction. Encouragingly, the new radii parameters also outperform old ones in SFE prediction using other charge methods, which proves that this new set of parameters can improve the MM/PBSA SFE prediction universally. Furthermore, we developed a new algorithm which enabled us to model the two major sources of the nonpolar HSE, the cavity term and the van der Waals interaction between the solute and solvent for non-aqueous systems. With this novel algorithm, we could accurately predict solvation free energy of solutes in an organic solvent, such as n-octanol. The accurate calculation of free energy of transfer can facilitate us to calculate logarithm of partition coefficient (logP) for arbitrary organic and pharmaceutical molecules with high accuracy.

Evaluation of the new ABCG2 charge model on solvation free energy (SFE) prediction and optimization of atom radii suitable for more accurate SFE prediction by MM/PBSA method

ACS Spring 2022

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