BUILDING MOLECULAR CHARGE-DISTRIBUTIONS FROM FRAGMENTS - APPLICATION TO HIV-1 PROTEASE INHIBITORS

Interaction energies are a function of the molecular charge distributi on. In previous work, we found that the set of atomic partial charges giving the best agreement with experimental vacuum dipole moments were from density functional theory calculations using an extended basis s et. Extension of such computations to larger molecules requires an ato mic partial charge calculation beyond present computational resources. A solution to this problem is the calculation of atomic partial charg es for segments of the molecule and reassociation of such fragments to yield partial charges for the entire molecule. Various partitions and reassociation methods for five molecules relevant to HIV-1 protease i nhibitors are examined. A useful method of reassociation is introduced in which atomic partial charges for a large molecule are computed by fitting to the combined electrostatic potential calculated from the fr agment partial charges. As expected, the best sites for partitions are shown to be carbon-carbon rather than carbon-nitrogen bonds. (C) 1997 by John Wiley & Sons, Inc.