ATOMIC CHARGES FOR VARIABLE MOLECULAR-CONFORMATIONS

The problem of generating high-quality atomic charges valid over a range of conformations has been addressed using two related methods which both employ a constrained minimization of the difference between the quantum mechanical and classical MEP (molecular electrostatic potential) with respect to the atomic charges. The first method involves determining the MEP and constraining the charges to reproduce the dipole at an alternative geometry. The second method involves determining the MEP for each conformation of interest and weighting the MEP for each conformation according to the appropriate Boltzmann factor. These methods offer considerable improvement over averaging the charges obtained at each conformation. The improvement in the performance of these multiple conformation MEP derived charges is illustrated by studying the variation of the classical dipole with conformation and comparing the results with those from ab initio calculations. It is proposed that the main use of these multiple conformation MEP derived charges and dipole constrained charges is likely to be in computer simulations where the ability to search conformational space is matched by the ability of the charges to yield the correct electrostatic properties at the conformations of interest. The errors arising from ignoring these effects have been assessed by evaluating the hydration free energy using a continuum method and are found to be significant. The extension of these methods to protein simulations is discussed.