TOWARD IMPROVED FORCE-FIELDS .1. MULTIPOLE-DERIVED ATOMIC CHARGES

The electrostatic energy component of classical force fields often inc ludes some of the polarization energy component implicitly through the choice of atomic charges. In this and the subsequent articles we desc ribe progress toward separating and accurately calculating both electr ostatic and polarization energies. In the present contribution the dis tributed point charge representation of electrostatics is retained. Ch arges derived from several quantum chemical models including electron correlation at various levels are compared. We found that ignoring ele ctron correlation in deriving charges for our force field can result i n an error of several kcal mol-l in free energy difference simulations , and that this error can be comparable to the effect of ignoring pola rization. We conclude that the accurate treatment of polarization in f orce fields also requires an accurate treatment of electron correlatio n. The work is based on the relatively new MPFIT charge fitting proced ure (Ferenczy, G. G. J. Comput. Chem. 1991, 12, 913; Chipot, C.; et. a l. J. Phys. Chem. 1993, 97, 6628), which produces point charges compar able to conventional molecular electrostatic potential-derived charges . These new charges are slightly less polar and more transferable and contain more chemical sense, but they are still conformationally depen dent. The significance of different levels of electron correlation in these charges was examined through regression analysis, to determine s caling relationships between the charges, and through free energy diff erence simulations, to determine the effect of using alternative charg e sets. The free energy calculations indicate that the Becke-Lee, Yang , and Parr nonlocal density functional method gives charges similar to second-order Moller-Plessett perturbation theory. The charges are sho wn to be insensitive to the precision of the quadrature used in the de nsity functional calculations. For polar molecules, these methods gene rally gave free energies of hydration which were significantly smaller than those computed using Hartree-Fock charges. When the Hartree-Fock charges are scaled to reproduce the higher quality charges, the error is usually reduced, but is still significant in some cases. Since man y force fields effectively exploit the polarity of the Hartree-Fock ch arges to mimic the effects of polarization in an ad hoc way, this resu lt has important implications for force field design, as mentioned abo ve. It is suggested that the electron density calculated by the densit y functional method is a suitable starling point to derive distributed multipole sets for use in force fields which include explicit polariz ation.