Optimal scaling factors for CM1 and CM3 atomic charges in RM1‐based aqueous simulations

Abstract

Scaling factors for atomic charges derived from the RM1 semiempirical quantum mechanical wavefunction in conjunction with CM1 and CM3 charge models have been optimized by minimizing errors in absolute free energies of hydration, ΔG(hyd) , for a set of 40 molecules. Monte Carlo statistical mechanics simulations and free energy perturbation theory were used to annihilate the solutes in gas and in a box of TIP4P water molecules. Lennard-Jones parameters from the optimized potentials for liquid simulations-all atom (OPLS-AA) force field were utilized for the organic compounds. Optimal charge scaling factors have been determined as 1.11 and 1.14 for the CM1R and CM3R methods, respectively, and the corresponding unsigned average errors in ΔG(hyd) relative to experiment were 2.05 and 1.89 kcal/mol. Computed errors in aniline and two derivatives were particularly large for RM1 and their removal from the data set lowered the overall errors to 1.61 and 1.75 kcal/mol for CM1R and CM3R. Comparisons are made to the AM1 method which yielded total errors in ΔG(hyd) of 1.50 and 1.64 kcal/mol for CM1A*1.14 and CM3A*1.15, respectively. This work is motivated by the need for a highly efficient yet accurate quantum mechanical (QM) method to study condensed-phase and enzymatic chemical reactions via mixed QM and molecular mechanical (QM/MM) simulations. As an initial test, the Menshutkin reaction between NH(3) and CH(3) Cl in water was computed using a RM1/TIP4P-Ew/CM3R procedure and the resultant ΔG(‡) , ΔG(rxn) , and geometries were in reasonable accord with other computational methods; however, some potentially serious shortcomings in RM1 are discussed.