Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 2000 Mar;78(3):1094–1105. doi: 10.1016/S0006-3495(00)76668-9

Kinetics of desolvation-mediated protein-protein binding.

C J Camacho 1, S R Kimura 1, C DeLisi 1, S Vajda 1
PMCID: PMC1300713  PMID: 10692300

Abstract

The role of desolvation in protein binding kinetics is investigated using Brownian dynamics simulations in complexes in which the electrostatic interactions are relatively weak. We find that partial desolvation, modeled by a short-range atomic contact potential, is not only a major contributor to the binding free energy but also substantially increases the diffusion-limited rate for complexes in which long-range electrostatics is weak. This rate enhancement is mostly due to weakly specific pathways leading to a low free-energy attractor, i.e., a precursor state before docking. For alpha-chymotrypsin and human leukocyte elastase, both interacting with turkey ovomucoid third domain, we find that the forward rate constant associated with a collision within a solid angle varphi around their corresponding attractor approaches 10(7) and 10(6) M(-1)s(-1), respectively, in the limit phi approximately 2 degrees. Because these estimates agree well with experiments, we conclude that the final bound conformation must be preceded by a small set of well-defined diffusion-accessible precursor states. The inclusion of the otherwise repulsive desolvation interaction also explains the lack of aggregation in proteins by restricting nonspecific association times to approximately 4 ns. Under the same reaction conditions but without short range forces, the association rate would be only approximately 10(3) M(-1)s(-1). Although desolvation increases these rates by three orders of magnitude, desolvation-mediated association is still at least 100-fold slower than the electrostatically assisted binding in complexes such as barnase and barstar.

Full Text

The Full Text of this article is available as a PDF (150.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ardelt W., Laskowski M., Jr Turkey ovomucoid third domain inhibits eight different serine proteinases of varied specificity on the same ...Leu18-Glu19 ... reactive site. Biochemistry. 1985 Sep 24;24(20):5313–5320. doi: 10.1021/bi00341a007. [DOI] [PubMed] [Google Scholar]
  2. Berg O. G. Orientation constraints in diffusion-limited macromolecular association. The role of surface diffusion as a rate-enhancing mechanism. Biophys J. 1985 Jan;47(1):1–14. doi: 10.1016/S0006-3495(85)83870-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Camacho C. J., Weng Z., Vajda S., DeLisi C. Free energy landscapes of encounter complexes in protein-protein association. Biophys J. 1999 Mar;76(3):1166–1178. doi: 10.1016/S0006-3495(99)77281-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chothia C., Janin J. Principles of protein-protein recognition. Nature. 1975 Aug 28;256(5520):705–708. doi: 10.1038/256705a0. [DOI] [PubMed] [Google Scholar]
  5. DeLisi C. The biophysics of ligand-receptor interactions. Q Rev Biophys. 1980 May;13(2):201–230. doi: 10.1017/s0033583500001657. [DOI] [PubMed] [Google Scholar]
  6. DeLisi C., Wiegel F. W. Effect of nonspecific forces and finite receptor number on rate constants of ligand--cell bound-receptor interactions. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5569–5572. doi: 10.1073/pnas.78.9.5569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eisenberg D., McLachlan A. D. Solvation energy in protein folding and binding. Nature. 1986 Jan 16;319(6050):199–203. doi: 10.1038/319199a0. [DOI] [PubMed] [Google Scholar]
  8. Eltis L. D., Herbert R. G., Barker P. D., Mauk A. G., Northrup S. H. Reduction of horse heart ferricytochrome c by bovine liver ferrocytochrome b5. Experimental and theoretical analysis. Biochemistry. 1991 Apr 16;30(15):3663–3674. doi: 10.1021/bi00229a011. [DOI] [PubMed] [Google Scholar]
  9. Gabdoulline R. R., Wade R. C. Simulation of the diffusional association of barnase and barstar. Biophys J. 1997 May;72(5):1917–1929. doi: 10.1016/S0006-3495(97)78838-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Israelachvili J., Wennerström H. Role of hydration and water structure in biological and colloidal interactions. Nature. 1996 Jan 18;379(6562):219–225. doi: 10.1038/379219a0. [DOI] [PubMed] [Google Scholar]
  11. Janin J. The kinetics of protein-protein recognition. Proteins. 1997 Jun;28(2):153–161. doi: 10.1002/(sici)1097-0134(199706)28:2<153::aid-prot4>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  12. Lee B., Richards F. M. The interpretation of protein structures: estimation of static accessibility. J Mol Biol. 1971 Feb 14;55(3):379–400. doi: 10.1016/0022-2836(71)90324-x. [DOI] [PubMed] [Google Scholar]
  13. Lombardi V., Piazzesi G., Linari M. Rapid regeneration of the actin-myosin power stroke in contracting muscle. Nature. 1992 Feb 13;355(6361):638–641. doi: 10.1038/355638a0. [DOI] [PubMed] [Google Scholar]
  14. Northrup S. H., Erickson H. P. Kinetics of protein-protein association explained by Brownian dynamics computer simulation. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3338–3342. doi: 10.1073/pnas.89.8.3338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Schreiber G., Fersht A. R. Rapid, electrostatically assisted association of proteins. Nat Struct Biol. 1996 May;3(5):427–431. doi: 10.1038/nsb0596-427. [DOI] [PubMed] [Google Scholar]
  16. Sharp K., Fine R., Honig B. Computer simulations of the diffusion of a substrate to an active site of an enzyme. Science. 1987 Jun 12;236(4807):1460–1463. doi: 10.1126/science.3589666. [DOI] [PubMed] [Google Scholar]
  17. Sommer J., Jonah C., Fukuda R., Bersohn R. Production and subsequent second-order decomposition of protein disulfide anions lengthy collisions between proteins. J Mol Biol. 1982 Aug 25;159(4):721–744. doi: 10.1016/0022-2836(82)90110-3. [DOI] [PubMed] [Google Scholar]
  18. Stone S. R., Dennis S., Hofsteenge J. Quantitative evaluation of the contribution of ionic interactions to the formation of the thrombin-hirudin complex. Biochemistry. 1989 Aug 22;28(17):6857–6863. doi: 10.1021/bi00443a012. [DOI] [PubMed] [Google Scholar]
  19. Vajda S., Weng Z., Rosenfeld R., DeLisi C. Effect of conformational flexibility and solvation on receptor-ligand binding free energies. Biochemistry. 1994 Nov 29;33(47):13977–13988. doi: 10.1021/bi00251a004. [DOI] [PubMed] [Google Scholar]
  20. Vijayakumar M., Wong K. Y., Schreiber G., Fersht A. R., Szabo A., Zhou H. X. Electrostatic enhancement of diffusion-controlled protein-protein association: comparison of theory and experiment on barnase and barstar. J Mol Biol. 1998 May 22;278(5):1015–1024. doi: 10.1006/jmbi.1998.1747. [DOI] [PubMed] [Google Scholar]
  21. Wolfenden R., Andersson L., Cullis P. M., Southgate C. C. Affinities of amino acid side chains for solvent water. Biochemistry. 1981 Feb 17;20(4):849–855. doi: 10.1021/bi00507a030. [DOI] [PubMed] [Google Scholar]
  22. Zhang C., Vasmatzis G., Cornette J. L., DeLisi C. Determination of atomic desolvation energies from the structures of crystallized proteins. J Mol Biol. 1997 Apr 4;267(3):707–726. doi: 10.1006/jmbi.1996.0859. [DOI] [PubMed] [Google Scholar]
  23. Zhou H. X. Enhancement of protein-protein association rate by interaction potential: accuracy of prediction based on local Boltzmann factor. Biophys J. 1997 Nov;73(5):2441–2445. doi: 10.1016/S0006-3495(97)78272-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. von Hippel P. H., Berg O. G. On the specificity of DNA-protein interactions. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1608–1612. doi: 10.1073/pnas.83.6.1608. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES