Development of a Simple Electron Transfer and Polarization Model and Its Application to Biological Systems.

Abstract

Here we present a new method for point charge calculation which we call QET (charges by electron transfer). The intent of this work is to develop a method that can be useful for studying charge transfer in large biological systems. It is based on the intuitive framework of the QEQ method with the key difference being that the QET method tracks all pairwise electron transfers by augmenting the QEQ pseudoenergy function with a distance dependent cost function for each electron transfer. This approach solves the key limitation of the QEQ method which is its handling of formally charged groups. First, we parametrize the QET method by fitting to electrostatic potentials calculated using ab initio quantum mechanics on over 11,000 small molecules. On an external test set of over 2500 small molecules the QET method achieves a mean absolute error of 1.37 kcal/mol/electron when compared to the ab initio electrostatic potentials. Second, we examine the conformational dependence of the charges on over 2700 tripeptides. With the tripeptide data set, we show that the conformational effects account for approximately 0.4 kcal/mol/electron on the electrostatic potentials. Third, we test the QET method for its ability to reproduce the effects of polarization and electron transfer on 1000 water clusters. For the water clusters, we show that the QET method captures about 50% of the polarization and electron transfer effects. Finally, we examine the effects of electron transfer and polarizability on the electrostatic interaction between p38 and 94 small molecule ligands. When used in conjunction with the Generalized-Born continuum solvent model, polarization and electron transfer with the QET model lead to an average change of 17 kcal/mol on the calculated electrostatic component of ΔG.