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 pot ential derived charges is that they optimally reproduce the intermolec ular interaction properties of molecules with a simple two-body additi ve potential, provided, of course, that a suitably accurate level of q uantum mechanical calculation is used to derive the ESP around the mol ecule. Previously, the major weaknesses of these charges have been tha t they were not easily transferable between common functional groups i n related molecules, they have often been conformationally dependent, and the large charges that frequently occur can be problematic for sim ulating intramolecular interactions. Introducing restraints in the for m of a penalty function into the fitting process considerably reduces the above problems, with only a minor decrease in the quality of the f it to the quantum mechanical ESP. Several other refinements in additio n 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 calculatio ns for any organic or bioorganic system.