We have developed a generalized Born based continuum dielectric model which incorporates a number of novel methodological advances, including an improved hydrophobic scoring term and a variable dielectric model to take into account enhanced polarization of solute atoms by charged groups. The model is optimized using a training set of single side chain prediction test cases from high resolution protein structures, and is then applied to the prediction of long loop regions, loop-helix-loop and hairpin structures, and the structures and binding affinities of protein-ligand complexes.  RMSDs for loops up to 20 residues in the range of 0.5-1.5A are demonstrated, along with consistent, accurate prediction of protein-ligand binding affinities for ~10 lead optimization series. Comparisons with alternative approaches  reveal significant improvements in performance.

VSGB 2.0 continuum dielectric model: Application to protein structure prediction and refinement and calculation of protein-ligand binding affinities

244th National Meeting (2012)

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