Journal of Molecular Modeling

, Volume 10, Issue 1, pp 44–54 | Cite as

Structure-based method for analyzing protein–protein interfaces

Original Paper


Hydrogen bond, hydrophobic and vdW interactions are the three major non-covalent interactions at protein–protein interfaces. We have developed a method that uses only these properties to describe interactions between proteins, which can qualitatively estimate the individual contribution of each interfacial residue to the binding and gives the results in a graphic display way. This method has been applied to analyze alanine mutation data at protein–protein interfaces. A dataset containing 13 protein–protein complexes with 250 alanine mutations of interfacial residues has been tested. For the 75 hot-spot residues (ΔΔG≥1.5 kcal mol-1), 66 can be predicted correctly with a success rate of 88%. In order to test the tolerance of this method to conformational changes upon binding, we utilize a set of 26 complexes with one or both of their components available in the unbound form. The difference of key residues exported by the program is 11% between the results using complexed proteins and those from unbound ones. As this method gives the characteristics of the binding partner for a particular protein, in-depth studies on protein–protein recognition can be carried out. Furthermore, this method can be used to compare the difference between protein–protein interactions and look for correlated mutation.

Figure Key interaction grids at the interface between barnase and barstar. Key interaction grid for barnase and barstar are presented in one figure according to their coordinates. In order to distinguish the two proteins, different icons were assigned. Crosses represent key grids for barstar and dots represent key grids for barnase. The four residues in ball and stick are Asp40 in barstar and Arg83, Arg87, His102 in barnase.


Protein–protein interaction Interface analysis Hot spot Correlated mutation PP_SITE 



This work has been supported by the Ministry of Science and Technology of China (the 863 High-tech project and the Basic Research Project 2003CB715900), the National Natural Science Foundation of China and The Committee of Science and Technology of Beijing.


  1. 1.
    Lichtarge O, Sowa ME (2002) Curr Opin Struct Biol 12:21–27Google Scholar
  2. 2.
    Bock JR, Gough DA (2001) Bioinformatics 17:455–460CrossRefPubMedGoogle Scholar
  3. 3.
    Kini RM, Evans HJ (1995) Biochem Biophys Res Commun 212:1115–1124CrossRefPubMedGoogle Scholar
  4. 4.
    Casari G, Sander C, Valencia A (1995) Nat Struct Biol 2:171–178PubMedGoogle Scholar
  5. 5.
    Pazos F, Helmer-Citterich M, Ausiello G, Valencia A (1997) J Mol Biol 271:511–523PubMedGoogle Scholar
  6. 6.
    Gallet X, Charloteaux B, Thomas A, Brasseur R (2000) J Mol Biol 302:917–926CrossRefPubMedGoogle Scholar
  7. 7.
    Madabushi S, Yao H, Marsh M, Kristensen DM, Philippi A, Sowa ME, Lichtarge O (2002) J Mol Biol 316:139–154CrossRefPubMedGoogle Scholar
  8. 8.
    Aloy P, Russell RB (2002) Proc Natl Acad Sci USA 99:5896–5901CrossRefPubMedGoogle Scholar
  9. 9.
    Aloy P, Russell RB (2003) Bioinformatics 19:161–162CrossRefPubMedGoogle Scholar
  10. 10.
    Zhou HX, Shan Y (2001) Proteins 44:336–343CrossRefPubMedGoogle Scholar
  11. 11.
    Fariselli P, Pazos F, Valencia A, Casadio R (2002) Eur J Biochem 269:1356–1361CrossRefPubMedGoogle Scholar
  12. 12.
    Pupko T, Bell RE, Mayrose I, Glaser F, Ben-Tal N (2002) Bioinformatics 18 Suppl 1:S71–7Google Scholar
  13. 13.
    Wells JA (1991) Methods Enzymology 202:390–411Google Scholar
  14. 14.
    Clackson T, Wells JA (1995) Science 267:383–386PubMedGoogle Scholar
  15. 15.
    Bogan AA, Thorn KS (1998) J Mol Biol 280:1–9CrossRefPubMedGoogle Scholar
  16. 16.
    Thorn KS, Bogan AA (2001) Bioinformatics 17:284–285CrossRefPubMedGoogle Scholar
  17. 17.
    Jones S, Thornton JM (1996) Proc Natl Acad Sci USA 93:13–20PubMedGoogle Scholar
  18. 18.
    Lo Conte L, Chothia C, Janin J (1999) J Mol Biol 285:2177–2198CrossRefPubMedGoogle Scholar
  19. 19.
    Elcock AH, Sept D, McCammon JA (2001) J Phys Chem B 105:1504–1518CrossRefGoogle Scholar
  20. 20.
    Massova I, Kollman PA (1999) J Am Chem Soc 121:8133–8143CrossRefGoogle Scholar
  21. 21.
    Huo S, Massova I, Kollman PA (2002) J Comput Chem 23:15–27CrossRefPubMedGoogle Scholar
  22. 22.
    Verkhivker GM, Bouzida D, Gehlhaar DK, Rejto PA, Freer ST, Rose PW (2002) Proteins 48:539–557CrossRefPubMedGoogle Scholar
  23. 23.
    Hu ZJ, Ma BY, Wolfson H, Nussinov R (2000) Proteins 39:331–342CrossRefPubMedGoogle Scholar
  24. 24.
    Young L, Jernigan RL, Covell DG. (1994) Protein Sci 3:717–729PubMedGoogle Scholar
  25. 25.
    Villoutreix BO, Hardig Y, Wallqvist A, Covell DG, Frutos PG (1998) Proteins 31:391–405CrossRefPubMedGoogle Scholar
  26. 26.
    Villoutreix BO, Covell DG, Blom AM, Wallqvist A, Friedrich U (2001) J Comput-Aided Mol Des 15:13–27Google Scholar
  27. 27.
    Goodford PJ (1985) J Med Chem 28:849–857PubMedGoogle Scholar
  28. 28.
    Gao Y, Wang RX, Lai LH (2002) Acta Phys-Chim Sin 18:676–679Google Scholar
  29. 29.
    Myers EW, Miller W (1989) Bull Math Biol 51:5–37PubMedGoogle Scholar
  30. 30.
    Delano WL (2002) Curr Opin Struct Biol 12:14–20Google Scholar
  31. 31.
    Betts MJ, Sternberg MJ (1999) Protein Eng 12:271–283CrossRefPubMedGoogle Scholar
  32. 32.
    Wang RX, Gao Y, Lai LH (2000) J Mol Model 6:498-516Google Scholar
  33. 33.
    Wang RX, Liu L, Lai LH, Tang YQ (1998) J Mol Model 4:379–394CrossRefGoogle Scholar
  34. 34.
    Wang RX, Gao Y, Lai LH (2000) Perspect Drug Discovery 19:47–66CrossRefGoogle Scholar
  35. 35.
    Buckle AM, Chreiber GS, Fersht AR (1994) Biochem 33:8878–8889PubMedGoogle Scholar
  36. 36.
    Schreiber G, Fersht AR (1995) J Mol Biol 248:478–486CrossRefPubMedGoogle Scholar
  37. 37.
    Covell DG, Wallqvist A (1997) J Mol Biol 269:281–297CrossRefPubMedGoogle Scholar
  38. 38.
    Böttger A, Böttger V, Garcia-Echeverria C, Chène P, Hochkeppel HK, Sampson W, Ang K, Howard SF, Picksley SM, Lane DP (1997) J Mol Biol 269:744–756CrossRefPubMedGoogle Scholar
  39. 39.
    DeLano WL, Ultsch MH, de Vos AM, Wells JM (2000) Science 287:1279–1283CrossRefPubMedGoogle Scholar
  40. 40.
    Tong L, Pav S, Pargellis C, Do F, Lamarre D, Anderson PC (1993) Proc Natl Acad Sci USA 90:8387–8391PubMedGoogle Scholar
  41. 41.
    Goldman ER, Dall’Acqua W, Braden BC, Mariuzza RA (1997) Biochem 36:49–56CrossRefGoogle Scholar
  42. 42.
    Dall’Acqua W, Goldman ER, Eisenstein E, Mariuzza RA (1996) Biochem 35:9667–9676CrossRefGoogle Scholar
  43. 43.
    Dall’Acqua W, Goldman ER, Lin W, Teng C, Tsuchiya D, Li HM, Ysern X, Braden BC, Li YL, Smith-Gill SJ, Mariuzza RA (1998) Biochem 37:7981–7991CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.State Key Laboratory of Structural Chemistry for Stable and Unstable Species, College of Chemistry and Molecular EngineeringPeking UniversityBeijingChina
  2. 2.Center for Theoretical BiologyPeking UniversityBeijingChina
  3. 3.Medical Chemistry and Comprehensive Cancer CenterUniversity of MichiganUSA

Personalised recommendations