Effective Approximation of Molecular Volume Using Atom-Centered Dielectric Functions in Generalized Born Models

The generalized Born (GB) theory is a prime choice for implicit treatment of solvent that provides a favorable balance between efficiency and accuracy for reliable simulation of protein conformational equilibria. In GB, the dielectric boundary is a key physical property that needs to be properly described. While it is widely accepted that the molecular surface (MS) should provide the most physical description, most existing GB models are based on van der Waals (vdW)-like surfaces for computational simplicity and efficiency. A simple and effective approximation to molecular volume is explored here using atom-centered dielectric functions within the context of a generalized Born model with simple switching (GBSW). The new model, termed GBSW/MS2, is as efficient as the original vdW-like-surface-based GBSW model, but is able to reproduce the Born radii calculated from the exact Poisson Boltzmann theory with a correlation of 0.95. More importantly, examination of the potentials of mean force of hydrogen-bonding and charge charge interactions demonstrates that GBSW/MS2 correctly captures the first desolvation peaks, a key signature of true MS. Physical parameters including atomic input radii and peptide backbone torsion were subsequently optimized on the basis of solvation free energies of model compounds, potentials of mean force of their interactions, and conformational equilibria of a set of helical and beta-hairpin model peptides. The resulting GBSW/MS2 protein force field reasonably recapitulates the structures and stabilities of these model peptides. Several remaining limitations and possible future developments are also discussed.