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Article

Generalized Born Model with a Simple, Robust Molecular Volume Correction

John Mongan,^†^‡^§ Carlos Simmerling,^# J. Andrew McCammon,^†^§ David A. Case,^§ and Alexey Onufriev*

Bioinformatics Program, Medical Scientist Training Program, Center for Theoretical Biological Physics, Department of Chemistry and Biochemistry, and Department of Pharmacology, UC San Diego, La Jolla, California 92093-0365, Department of Chemistry and Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794-3400, Howard Hughes Medical Institute, Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, and Departments of Computer Science and Physics, Virginia Tech, Blacksburg, Virginia 24060

J. Chem. Theory Comput., 2007, 3 (1), pp 156–169

DOI: 10.1021/ct600085e

Publication Date (Web): December 8, 2006

†

Bioinformatics Program, UC San Diego.

‡

Medical Scientist Training Program, UC San Diego.

Center for Theoretical Biological Physics, UC San Diego.

Stony Brook University.

Department of Chemistry and Biochemistry, UC San Diego.

Department of Pharmacology, UC San Diego.

The Scripps Research Institute.

Corresponding author e-mail: alexey@cs.vt.edu.

Virginia Tech.

Abstract

Generalized Born (GB) models provide a computationally efficient means of representing the electrostatic effects of solvent and are widely used, especially in molecular dynamics (MD). A class of particularly fast GB models is based on integration over an interior volume approximated as a pairwise union of atom sphereseffectively, the interior is defined by a van der Waals rather than Lee-Richards molecular surface. The approximation is computationally efficient but, if uncorrected, allows for high dielectric (water) regions smaller than a water molecule between atoms, leading to decreased accuracy. Here, an earlier pairwise GB model is extended by a simple analytic correction term that largely alleviates the problem by correctly describing the solvent-excluded volume of each pair of atoms. The correction term introduces a free energy barrier to the separation of nonbonded atoms. This free energy barrier is seen in explicit solvent and Lee-Richards molecular surface implicit solvent calculations but has been absent from earlier pairwise GB models. When used in MD, the correction term yields protein hydrogen bond length distributions and polypeptide conformational ensembles that are in better agreement with explicit solvent results than earlier pairwise models. The robustness and simplicity of the correction preserves the efficiency of the pairwise GB models while making them a better approximation to reality.