High-Throughput Prediction of the Hydration Free Energies of Small Molecules from a Classical Density Functional Theory

Abstract

The classical density functional theory (DFT) is proposed as an efficient computational tool for high-throughput prediction of the solvation free energies of small molecules in liquid water under the ambient condition. With the solute molecules represented by the AMBER force field and the TIP3P model for the solvent, the new theoretical method predicts the hydration free energies of 500 neutral molecules with average unsigned errors of 0.96 and 1.04 kcal/mol in comparison with the experimental and simulation data, respectively. The DFT predictions are orders of magnitude faster than conventional molecular dynamics simulations, and the theoretical performance can be further improved by taking into account the molecular flexibility of large solutes.

Toward high-throughput predictions of the hydration free energies of small organic molecules from first principles

“…In previous publications [97,103], we demonstrated that the MDFT is able to reproduce the simulation data for the hydration free energies of hundreds of chemicals. For the hydration free energies of about 700 small molecules, the MDFT calculation yields an average unsigned error (AUE) of 1.35 kcal/mol compared to experimental data.…”

“…This assumption becomes problematic for large hydrophilic molecules that exhibit significant backbone flexibility. It has been shown that the molecular structure may have a drastic effect on the solvation free energy [97]. For better theoretical performance, we may account for the flexibility effect by considering a relatively small number of solute conformations.…”

“…The theoretical details for MDFT calculations can be found in our previous publications [97,98,100,103]. Here we highlight only the key equations and the generic procedure for its numerical implementation.…”

“…In addition to molecular simulations, both integral-equation and classical density functional theories (DFTs) can be used to predict solvation free energy on the basis of an atomistic description of the molecular systems [88][89][90][91][92][93][94][95][96][97][98][99][100]. To a certain degree, liquid-state methods represent a good compromise between continuous approaches and molecular simulations.…”

“…With the bridge functional represented by the modified fundamental measure theory (MFMT) [101,102], MDFT allows us to predict the solvation structure and the solvation free energy in excellent agreement with molecular simulations [97,98,100,103]. A main purpose of this work is to examine the MDFT performance in comparison to experimental data for the hydration free energies of 2583 neutral organic molecules.…”