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Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains

Abstract

Amino acids have sidechain rotamer preferences dependent on the backbone dihedral angles φ and ψ. These preferences provide a method for rapid structure prediction which is a significant improvement over backbone-independent rotamer libraries. We demonstrate here that simple arguments based on conformational analysis can account for many of the features of the observed backbone dependence of the sidechain rotamers. Steric repulsions corresponding to the ‘butane’ and ‘syn-pentane’ effects make certain conformers rare, as has been observed experimentally.

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References

  1. Chandrasekaran, R. & Ramachandran, G.N. Studies on the conformation of amino acids. XI. Analysis of the observed side group conformations in proteins. Int. J. prot. Res. 2, 223–233 (1970).

    Article  CAS  Google Scholar 

  2. Janin, J., Wodak, S., Levitt, M. & Maigret, B. Conformations of amino acid sidechains in proteins. J. molec. Biol. 125, 357–386 (1978).

    Article  CAS  Google Scholar 

  3. Ponder, J.W. & Richards, F.M. Tertiary templates for proteins: Use of packing criteria in the enumeration of allowed sequences for different structural classes. J. molec. Biol. 193, 775–792 (1987).

    Article  CAS  Google Scholar 

  4. Bhat, T.N., Sasisekharan, V. & Vijayan, M. An analysis of side-chain conformation in proteins. Int. J. Peptide Protein Res. 13, 170–184 (1979).

    Article  CAS  Google Scholar 

  5. Benedetti, E., Morelli, G., Nemethy, G. & Scheraga, H.A. Statistical and energetic analysis of side-chain conformations in oligopeptides. Int. J. Peptide Protein Res. 22, 1–15 (1983).

    Article  CAS  Google Scholar 

  6. Tuffery, P., Etchebest, C., Hazout, S. & Lavery, R.A. A new approach to the rapid determination of protein side chain conformations. J. biomolec. Struct. Dyn. 8, 1267–1289 (1991).

    Article  CAS  Google Scholar 

  7. McGregor, M.J., Islam, S.A. & Sternberg, M.J.E. Analysis of the relationship between sidechain conformation and secondary structure in globular proteins. J. molec. Biol. 198, 295–310 (1987).

    Article  CAS  Google Scholar 

  8. Dunbrack, R.L., Jr & Karplus, M. Backbone-dependent rotamer library for proteins: Application to sidechain prediction. J. molec. Biol. 230, 543–571 (1993).

    Article  CAS  Google Scholar 

  9. Schrauber, H., Eisenhaber, F. & Argos, P. Rotamers: To be or not to be? An analysis of amino acid sidechain conformations in globular proteins. J. molec. Biol. 230, 592–612 (1993).

    Article  CAS  Google Scholar 

  10. Dunbrack, R.L., Jr Conformational analysis of protein sidechains: Empirical energy parameters for proline and development of a backbone-dependent rotamer library (Ph. D. Thesis, Harvard University, 1993).

    Google Scholar 

  11. Eisenmenger, F., Argos, P. & Abagyan, R. A method to configure protein sidechains from the mainchain trace in homology modeling. J. molec. Biol. 231, 849–860 (1993).

    Article  CAS  Google Scholar 

  12. Lee, C. & Subbiah, S. Prediction of protein sidechain conformation by packing optimization. J. molec. Biol. 217, 373–388 (1991).

    Article  CAS  Google Scholar 

  13. Desmet, J., DeMaeyer, M., Hazes, B. & Lasters, I. The dead-end elimination theorem and its use in protein sidechain positioning. Nature 356, 539–542 (1992).

    Article  CAS  Google Scholar 

  14. Becker, F., Theoretische Behandlung des Einflusses sterischer Effekte auf die Reaktivität aliphatischer Verbindungen I. Z. Naturforsch. 14a, 547–556 (1959).

    CAS  Google Scholar 

  15. Eliel, E.L., Allinger, N.A., Angyal, S.J. & Morrison, G.A. Conformational Analysis (Interscience, New York, 1965).

    Google Scholar 

  16. Ramachandran, G.N., Ramakrishnan, C. and Sasisekharan, V.J. Stereochemistry of polypeptide chain configurations, J. molec. Biol. 7, 95–99 (1963).

    Article  CAS  Google Scholar 

  17. Gelin, B.R. & Karplus, M. Sidechain torsional potentials: Effect of dipeptide, protein, and solvent environment. Biochemistry 18, 1256–1268 (1979).

    Article  CAS  Google Scholar 

  18. Ponnuswamy, P.K. & Sasisekharan, V. Studies on the conformation of amino acids. IX. Conformations of butyl, seryl, threonyl, cysteinyl, and valyl residues in a dipeptide unit. Biopolymers 10, 565–582 (1971).

    Article  CAS  Google Scholar 

  19. Lewis, P.N., Momany, F.A. & Scheraga, H.A. Energy parameters in polypeptides. VI. Conformational energy analysis of the N-Acetyl N′-methyl amides of the twenty naturally occurring amino acids. Israel. J. Chem. 11, 121–152 (1973).

    Article  CAS  Google Scholar 

  20. Zimmerman, S.S., Pottle, M.S., Nemethy, G. & Scheraga, H.A. Conformational analysis of the 20 naturally occurring amino acid residues using ECEPP. Macromolecules 10, 1–9 (1977).

    Article  CAS  Google Scholar 

  21. Compton, D.A.C., Montero, S. & Murphy, W.F., Low-frequency Raman spectrum and asymmetric potential function for internal rotation of gaseous n-butane. J. phys. Chem. 84, 3587–3591 (1980).

    Article  CAS  Google Scholar 

  22. Pitzer, K.S. The vibration frequencies and thermodynamic functions of long chain hydrocarbons. J. chem. Phys. 8, 711–720 (1940).

    Article  CAS  Google Scholar 

  23. Wiberg, K.B. & Murcko, M.A. Rotational barriers. 2. Energies of alkane rotamers. An examination of gauche interactions. J. Am. chem. Soc. 110, 8029–8038 (1988).

    Article  CAS  Google Scholar 

  24. Hoeve, C.A.J. Unperturbed mean-square end-to-end distance in polyethylene. J. chem. Phys. 35, 1266–1267 (1961).

    Article  CAS  Google Scholar 

  25. Abe, A., Jernigan, R.L. & Flory, P.J. Conformational energies of n-alkanes and the random configuration of higher homologs including polymethylene. J. Am. chem. Soc. 88, 631–639 (1966).

    Article  CAS  Google Scholar 

  26. Pitzer, K.S. Chemical equilibria, free energies, and heat contents for gaseous hydrocarbons. Chem. Rev. 27, 39–57 (1940).

    Article  CAS  Google Scholar 

  27. Pitzer, R.M. The barrier to internal rotation in ethane. Accts. chem. Res. 16, 201–210 (1983).

    Article  Google Scholar 

  28. Newman, M.S. A notation for the study of certain stereochemical problems. J. chem. Ed. 32, 344–347 (1955).

    Article  CAS  Google Scholar 

  29. Gray, T.M. & Matthews, B.W. Intrahelical hydrogen bonding of serine, threonine, and cysteine residues with α-helices and its relevance to membrane-bound proteins. J. molec. Biol. 175, 75–81 (1984).

    Article  CAS  Google Scholar 

  30. Brooks, B.R. et al. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. comp. Chem. 4, 187–217 (1983).

    Article  CAS  Google Scholar 

  31. Richards, F.M. & Lim, W.A. An analysis of packing in the protein folding problem. Q. Rev. Biophys. (in the press).

  32. Ferrin, T.E. et al. The MIDAS display system. J. molec. Graphics 6, 13–27 (1988).

    Article  CAS  Google Scholar 

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Dunbrack, R., Karplus, M. Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains. Nat Struct Mol Biol 1, 334–340 (1994). https://doi.org/10.1038/nsb0594-334

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