Biophys J, February 2001, p. 613-625, Vol. 80, No. 2

Calculation of Weak Protein-Protein Interactions: The pH Dependence of the Second Virial Coefficient

Department of Chemistry and Biochemistry, Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0365 USA

Interactions between proteins are often sufficiently weak that their study through the use of conventional structural techniques becomes problematic. Of the few techniques capable of providing experimental measures of weak protein-protein interactions, perhaps the most useful is the second virial coefficient, B₂₂, which quantifies a protein solution's deviations from ideal behavior. It has long been known that B₂₂ can in principle be computed, but only very recently has it been demonstrated that such calculations can be performed using protein models of true atomic detail (Biophys. J. 1998, 75:2469-2477). The work reported here extends these previous efforts in an attempt to develop a transferable energetic model capable of reproducing the experimental trends obtained for two different proteins over a range of pH and ionic strengths. We describe protein-protein interaction energies by a combination of three separate terms: (i) an electrostatic interaction term based on the use of effective charges, (ii) a term describing the electrostatic desolvation that occurs when charged groups are buried by an approaching protein partner, and (iii) a solvent-accessible surface area term that is used to describe contributions from van der Waals and hydrophobic interactions. The magnitude of the third term is governed by an adjustable, empirical parameter, , that is altered to optimize agreement between calculated and experimental values of B₂₂. The model is applied separately to the proteins lysozyme and chymotrypsinogen, yielding optimal values of  that are almost identical. There are, however, clear difficulties in reproducing B₂₂ values at the extremes of pH. Explicit calculation of the protonation states of ionizable amino acids in the 200 most energetically favorable protein-protein structures suggest that these difficulties are due to a neglect of the protonation state changes that can accompany complexation. Proper reproduction of the pH dependence of B₂₂ will, therefore, almost certainly require that account be taken of these protonation state changes. Despite this problem, the fact that almost identical  values are obtained from two different proteins suggests that the basic energetic formulation used here, which can be evaluated very rapidly, might find use in dynamical simulations of weak protein-protein interactions at intermediate pH values.

Biophys J, February 2001, p. 613-625, Vol. 80, No. 2
© 2001 by the Biophysical Society   0006-3495/01/02/613/13  $2.00

This article has been cited by other articles:

				A. Saluja, A. V. Badkar, D. L. Zeng, S. Nema, and D. S. Kalonia Ultrasonic Storage Modulus as a Novel Parameter for Analyzing Protein-Protein Interactions in High Protein Concentration Solutions: Correlation with Static and Dynamic Light Scattering Measurements Biophys. J., January 1, 2007; 92(1): 234 - 244. [Abstract] [Full Text] [PDF]

				A. Paliwal, D. Asthagiri, D. Abras, A. M. Lenhoff, and M. E. Paulaitis Light-Scattering Studies of Protein Solutions: Role of Hydration in Weak Protein-Protein Interactions Biophys. J., September 1, 2005; 89(3): 1564 - 1573. [Abstract] [Full Text] [PDF]

				V. M. Dadarlat Potentials of Mean Force for the Interaction of Blocked Alanine Dipeptide Molecules in Water and Gas Phase from MD Simulations Biophys. J., September 1, 2005; 89(3): 1433 - 1445. [Abstract] [Full Text] [PDF]

				R. F. Burton Temperature and acid--base balance in ectothermic vertebrates: the imidazole alphastat hypotheses and beyond J. Exp. Biol., December 1, 2002; 205(23): 3587 - 3600. [Abstract] [Full Text] [PDF]