Calculation of the total electrostatic energy of a macromolecular system: Solvation energies, binding energies, and conformational analysis

Abstract

In this report we describe an accurate numerical method for calculating the total electrostatic energy of molecules of arbitrary shape and charge distribution, accounting for both Coulombic and solvent polarization terms. In addition to the solvation energies of individual molecules, the method can be used to calculate the electrostatic energy associated with conformational changes in proteins as well as changes in solvation energy that accompany the binding of charged substrates. The validity of the method is examined by calculating the hydration energies of acetate, methyl ammonium, ammonium, and methanol. The method is then used to study the relationship between the depth of a charge within a protein and its interaction with the solvent. Calculations of the relative electrostatic energies of crystal and misfolded conformations of Themiste dyscritum hemerythrin and the VL domain of an antibody are also presented. The results indicate that electrostatic charge‐solvent interactions strongly favor the crystal structures. More generally, it is found that charge‐solvent interactions, which are frequently neglected in protein structure analysis, can make large contributions to the total energy of a macromolecular system.