Molecular mechanical models for organic and biological systems going beyond the atom centered two body additive approximation: aqueous solution free energies of methanol and N‐methyl acetamide, nucleic acid base, and amide hydrogen bonding and chloroform/water partition coefficients of the nucleic acid bases

TLDR

The study develops RESP charge methodology incorporating lone pairs and polarizabilities, and evaluates its performance on methanol, NMA solvation energies, nucleic acid base pair hydrogen bonding, and chloroform/water partition coefficients. The method employs a high‑level cc‑pVTZ ab initio calculation to self‑consistently derive RESP charges with lone pairs and polarizabilities, ensuring the model’s electrostatic potential matches the quantum mechanical potential. The enhanced model accurately reproduces methanol and NMA solvation free energies, improves chloroform/water partition coefficients relative to the additive model without parameter changes, and describes base‑pair hydrogen‑bond energies comparably to the additive model after adjusting the N–H van der Waals parameter. © 2001 John Wiley & Sons, Inc.; J Comput Chem 22: 1048–1057, 2001.

Abstract

Abstract We have developed a methodology to derive RESP charges for molecular mechanical models that include “lone pairs” on lone‐pair donor sites and atom‐centered polarizabilities. This approach uses a very high level ab initio cc‐pVTZ basis set, 1 where the multipole moments of the molecules are as accurate as possible. The partial charges are derived self‐consistently so that the model, whose electrostatic potential comes from both partial charges and induced dipoles, reproduces the quantum mechanical electrostatic potential. We then study the ability of such models to reproduce the aqueous solvation free energy of methanol and N‐methyl acetamide (NMA), the base pair hydrogen bonding of the 26 base pairs analyzed by Hobza et al. and the chloroform/water partition coefficients of the five N‐methyl substituted nucleic acid bases. The base pair H‐bond energies are described as well as the atom centered additive model, after modifying the van der Waals parameter on the NH to give reasonable base pair H‐bond distances. The experimental solvation free energies (gas→water) of methanol and NMA are well described, and the water/CHCl 3 partition coefficients are improved over the additive model, without any parameter changes. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1048–1057, 2001