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. 1997 Jul;6(7):1426–1437. doi: 10.1002/pro.5560060707

Hydrophobic folding units at protein-protein interfaces: implications to protein folding and to protein-protein association.

C J Tsai 1, R Nussinov 1
PMCID: PMC2143752  PMID: 9232644

Abstract

A hydrophobic folding unit cutting algorithm, originally developed for dissecting single-chain proteins, has been applied to a dataset of dissimilar two-chain protein-protein interfaces. Rather than consider each individual chain separately, the two-chain complex has been treated as a single chain. The two-chain parsing results presented in this work show hydrophobicity to be a critical attribute of two-state versus three-state protein-protein complexes. The hydrophobic folding units at the interfaces of two-state complexes suggest that the cooperative nature of the two-chain protein folding is the outcome of the hydrophobic effect, similar to its being the driving force in a single-chain folding. In analogy to the protein-folding process, the two-chain, two-state model complex may correspond to the formation of compact, hydrophobic nuclei. On the other hand, the three-state model complex involves binding of already folded monomers, similar to the association of the hydrophobic folding units within a single chain. The similarity between folding entities in protein cores and in two-state protein-protein interfaces, despite the absence of some chain connectivities in the latter, indicates that chain linkage does not necessarily affect the native conformation. This further substantiates the notion that tertiary, non-local interactions play a critical role in protein folding. These compact, hydrophobic, two-chain folding units, derived from structurally dissimilar protein-protein interfaces, provide a rich set of data useful in investigations of the role played by chain connectivity and by tertiary interactions in studies of binding and of folding. Since they are composed of non-contiguous pieces of protein backbones, they may also aid in defining folding nuclei.

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Selected References

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  1. Bennett M. J., Schlunegger M. P., Eisenberg D. 3D domain swapping: a mechanism for oligomer assembly. Protein Sci. 1995 Dec;4(12):2455–2468. doi: 10.1002/pro.5560041202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bernstein F. C., Koetzle T. F., Williams G. J., Meyer E. F., Jr, Brice M. D., Rodgers J. R., Kennard O., Shimanouchi T., Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977 May 25;112(3):535–542. doi: 10.1016/s0022-2836(77)80200-3. [DOI] [PubMed] [Google Scholar]
  3. Dill K. A. Dominant forces in protein folding. Biochemistry. 1990 Aug 7;29(31):7133–7155. doi: 10.1021/bi00483a001. [DOI] [PubMed] [Google Scholar]
  4. Eriksson A. E., Baase W. A., Zhang X. J., Heinz D. W., Blaber M., Baldwin E. P., Matthews B. W. Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect. Science. 1992 Jan 10;255(5041):178–183. doi: 10.1126/science.1553543. [DOI] [PubMed] [Google Scholar]
  5. Fersht A. R. Optimization of rates of protein folding: the nucleation-condensation mechanism and its implications. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):10869–10873. doi: 10.1073/pnas.92.24.10869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fischer D., Wolfson H., Lin S. L., Nussinov R. Three-dimensional, sequence order-independent structural comparison of a serine protease against the crystallographic database reveals active site similarities: potential implications to evolution and to protein folding. Protein Sci. 1994 May;3(5):769–778. doi: 10.1002/pro.5560030506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gittelman M. S., Matthews C. R. Folding and stability of trp aporepressor from Escherichia coli. Biochemistry. 1990 Jul 31;29(30):7011–7020. doi: 10.1021/bi00482a009. [DOI] [PubMed] [Google Scholar]
  8. Griko Y. V., Makhatadze G. I., Privalov P. L., Hartley R. W. Thermodynamics of barnase unfolding. Protein Sci. 1994 Apr;3(4):669–676. doi: 10.1002/pro.5560030414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hendsch Z. S., Tidor B. Do salt bridges stabilize proteins? A continuum electrostatic analysis. Protein Sci. 1994 Feb;3(2):211–226. doi: 10.1002/pro.5560030206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Holm L., Sander C. Parser for protein folding units. Proteins. 1994 Jul;19(3):256–268. doi: 10.1002/prot.340190309. [DOI] [PubMed] [Google Scholar]
  11. Islam S. A., Luo J., Sternberg M. J. Identification and analysis of domains in proteins. Protein Eng. 1995 Jun;8(6):513–525. doi: 10.1093/protein/8.6.513. [DOI] [PubMed] [Google Scholar]
  12. Lesk A. M., Rose G. D. Folding units in globular proteins. Proc Natl Acad Sci U S A. 1981 Jul;78(7):4304–4308. doi: 10.1073/pnas.78.7.4304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Liang H., Sandberg W. S., Terwilliger T. C. Genetic fusion of subunits of a dimeric protein substantially enhances its stability and rate of folding. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7010–7014. doi: 10.1073/pnas.90.15.7010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Moult J., Unger R. An analysis of protein folding pathways. Biochemistry. 1991 Apr 23;30(16):3816–3824. doi: 10.1021/bi00230a003. [DOI] [PubMed] [Google Scholar]
  15. Murphy K. P., Bhakuni V., Xie D., Freire E. Molecular basis of co-operativity in protein folding. III. Structural identification of cooperative folding units and folding intermediates. J Mol Biol. 1992 Sep 5;227(1):293–306. doi: 10.1016/0022-2836(92)90699-k. [DOI] [PubMed] [Google Scholar]
  16. Novokhatny V. V., Kudinov S. A., Privalov P. L. Domains in human plasminogen. J Mol Biol. 1984 Oct 25;179(2):215–232. doi: 10.1016/0022-2836(84)90466-2. [DOI] [PubMed] [Google Scholar]
  17. Nussinov R., Wolfson H. J. Efficient detection of three-dimensional structural motifs in biological macromolecules by computer vision techniques. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10495–10499. doi: 10.1073/pnas.88.23.10495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Privalov P. L. Intermediate states in protein folding. J Mol Biol. 1996 May 24;258(5):707–725. doi: 10.1006/jmbi.1996.0280. [DOI] [PubMed] [Google Scholar]
  19. Rashin A. A. Location of domains in globular proteins. Nature. 1981 May 7;291(5810):85–87. doi: 10.1038/291085a0. [DOI] [PubMed] [Google Scholar]
  20. Segawa S., Richards F. M. Identification of regions of potential flexibility in protein structures: folding units and correlations with intron positions. Biopolymers. 1988 Jan;27(1):23–40. doi: 10.1002/bip.360270103. [DOI] [PubMed] [Google Scholar]
  21. Siddiqui A. S., Barton G. J. Continuous and discontinuous domains: an algorithm for the automatic generation of reliable protein domain definitions. Protein Sci. 1995 May;4(5):872–884. doi: 10.1002/pro.5560040507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Sowdhamini R., Blundell T. L. An automatic method involving cluster analysis of secondary structures for the identification of domains in proteins. Protein Sci. 1995 Mar;4(3):506–520. doi: 10.1002/pro.5560040317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tasayco M. L., Carey J. Ordered self-assembly of polypeptide fragments to form nativelike dimeric trp repressor. Science. 1992 Jan 31;255(5044):594–597. doi: 10.1126/science.1736361. [DOI] [PubMed] [Google Scholar]
  24. Tegoni M., Ramoni R., Bignetti E., Spinelli S., Cambillau C. Domain swapping creates a third putative combining site in bovine odorant binding protein dimer. Nat Struct Biol. 1996 Oct;3(10):863–867. doi: 10.1038/nsb1096-863. [DOI] [PubMed] [Google Scholar]
  25. Tsai C. J., Lin S. L., Wolfson H. J., Nussinov R. A dataset of protein-protein interfaces generated with a sequence-order-independent comparison technique. J Mol Biol. 1996 Jul 26;260(4):604–620. doi: 10.1006/jmbi.1996.0424. [DOI] [PubMed] [Google Scholar]
  26. Tsai C. J., Lin S. L., Wolfson H. J., Nussinov R. Studies of protein-protein interfaces: a statistical analysis of the hydrophobic effect. Protein Sci. 1997 Jan;6(1):53–64. doi: 10.1002/pro.5560060106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Viguera A. R., Blanco F. J., Serrano L. The order of secondary structure elements does not determine the structure of a protein but does affect its folding kinetics. J Mol Biol. 1995 Apr 7;247(4):670–681. doi: 10.1006/jmbi.1994.0171. [DOI] [PubMed] [Google Scholar]
  28. Walls P. H., Sternberg M. J. New algorithm to model protein-protein recognition based on surface complementarity. Applications to antibody-antigen docking. J Mol Biol. 1992 Nov 5;228(1):277–297. doi: 10.1016/0022-2836(92)90506-f. [DOI] [PubMed] [Google Scholar]
  29. Wodak S. J., Janin J. Location of structural domains in protein. Biochemistry. 1981 Nov 10;20(23):6544–6552. doi: 10.1021/bi00526a005. [DOI] [PubMed] [Google Scholar]
  30. Wu L. C., Grandori R., Carey J. Autonomous subdomains in protein folding. Protein Sci. 1994 Mar;3(3):369–371. doi: 10.1002/pro.5560030301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Xu D., Lin S. L., Nussinov R. Protein binding versus protein folding: the role of hydrophilic bridges in protein associations. J Mol Biol. 1997 Jan 10;265(1):68–84. doi: 10.1006/jmbi.1996.0712. [DOI] [PubMed] [Google Scholar]
  32. Young L., Jernigan R. L., Covell D. G. A role for surface hydrophobicity in protein-protein recognition. Protein Sci. 1994 May;3(5):717–729. doi: 10.1002/pro.5560030501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zehfus M. H. Improved calculations of compactness and a reevaluation of continuous compact units. Proteins. 1993 Jul;16(3):293–300. doi: 10.1002/prot.340160307. [DOI] [PubMed] [Google Scholar]
  34. Zehfus M. H., Rose G. D. Compact units in proteins. Biochemistry. 1986 Sep 23;25(19):5759–5765. doi: 10.1021/bi00367a062. [DOI] [PubMed] [Google Scholar]

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