A WELL-BEHAVED ELECTROSTATIC POTENTIAL BASED METHOD USING CHARGE RESTRAINTS FOR DERIVING ATOMIC CHARGES - THE RESP MODEL

We present a new approach to generating electrostatic potential (ESP) derived charges for molecules. The major strength of electrostatic potential derived charges is that they optimally reproduce the intermolecular interaction properties of molecules with a simple two-body additive potential, provided, of course, that a suitably accurate level of quantum mechanical calculation is used to derive the ESP around the molecule. Previously, the major weaknesses of these charges have been that they were not easily transferable between common functional groups in related molecules, they have often been conformationally dependent, and the large charges that frequently occur can be problematic for simulating intramolecular interactions. Introducing restraints in the form of a penalty function into the fitting process considerably reduces the above problems, with only a minor decrease in the quality of the fit to the quantum mechanical ESP. Several other refinements in addition to the restrained electrostatic potential (RESP) fit yield a general and algorithmic charge fitting procedure for generating atom-centered point charges. This approach can thus be recommended for general use in molecular mechanics, molecular dynamics, and free energy calculations for any organic or bioorganic system.