Accuracy of free energies of hydration using CM1 and CM3 atomic charges

Abstract Absolute free energies of hydration (Δ G hyd ) have been computed for 25 diverse organic molecules using partial atomic charges derived from AM1 and PM3 wave functions via the CM1 and CM3 procedures of Cramer, Truhlar, and coworkers. Comparisons are made with results using charges fit to the electrostatic potential surface (EPS) from ab initio 6‐31G* wave functions and from the OPLS‐AA force field. OPLS Lennard–Jones parameters for the organic molecules were used together with the TIP4P water model in Monte Carlo simulations with free energy perturbation theory. Absolute free energies of hydration were computed for OPLS united‐atom and all‐atom methane by annihilating the solutes in water and in the gas phase, and absolute Δ G hyd values for all other molecules were computed via transformation to one of these references. Optimal charge scaling factors were determined by minimizing the unsigned average error between experimental and calculated hydration free energies. The PM3‐based charge models do not lead to lower average errors than obtained with the EPS charges for the subset of 13 molecules in the original study. However, improvement is obtained by scaling the CM1A partial charges by 1.14 and the CM3A charges by 1.15, which leads to average errors of 1.0 and 1.1 kcal/mol for the full set of 25 molecules. The scaled CM1A charges also yield the best results for the hydration of amides including the E/Z free‐energy difference for N ‐methylacetamide in water. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1322–1332, 2004