Abstract
NMR studies of the molecular conformations of peptides and proteins rely on a comparison of the relevant spectral parameters with the corresponding values for so-called statistical-coilpolypeptides. For this reason, it is necessary to characterize the experimental ensemble of states populated by statistical-coilpeptides. Such a characterization, however, has proven to be both difficult and sensitive to changes in many environmental parameters such as solvent composition, temperature, pH, as well as the neighboring amino acids in the sequence. As a consequence, a series of significant discrepancies has been reported for some experimentally observed parameters, such as chemical shifts, or vicinal coupling constants, 3JNHα, whose values appear to be incompatible with a statistical-coilensemble. In this work, we report the results of a molecular mechanics study of a series of unblocked tetra- and pentapeptides under different pH conditions. These calculations were carried out with explicit consideration of both the coupling between the process of proton binding/release and conformation adopted by the molecule at a given pH and the contribution of the conformational entropy to the total free energy. Good agreement was found between the calculated and experimentally determined values of the vicinal coupling constant, 3JNHα, the α-proton chemical shift, and the 13Cαchemical shift. All the evidence accumulated in these theoretical calculations helps to rationalize some of the unsettled anomalies observed experimentally, and to provide an understanding of the effect of pH and amino acid sequence on the conformational preferences of statistical-coilpeptides.
Similar content being viewed by others
References
Bagno, A. (2001) Chem. Eur. J., 7, 1652–1661.
Bashford, D. and Karplus, M. (1990) Biochemistry, 29, 10219–10225.
Becke, A.D. (1993) J. Chem. Phys., 98, 5648–5652.
Beroza, P., Fredkin, D.R., Okamura, M.Y. and Feher, G. (1995) Biophys. J., 68, 2233–2250.
Bundi, A. and Wüthrich, K. (1979a) Biopolymers, 18, 285–297.
Bundi, A. and Wüthrich, K. (1979b) Biopolymers, 18, 299–311.
Cheeseman, J.R., Trucks, G.W., Keith, T.A. and Frisch, M.J. (1996) J. Chem. Phys., 104, 5497–5509.
Chesnut, D.B. (1996) Rev. Comput. Chem., 8, 245–297.
De Marco, A., Llinás, M. and Wüthrich K. (1978) Biopolymers, 17, 617–636.
Ditchfield, R. (1974) Mol. Phys., 27, 789–807.
Dyson, H.J., Sayre, J.R., Merutka, G., Shin, H.-C., Lerner, R.A. and Wright, P.E. (1992) J. Mol. Biol. 226, 819–835.
Edsall, J.T. and Wyman J. (1958) In Biophysical Chemistry, Volume I, (Table IX), Academic Press Inc., New York, p. 536.
Facelli, J.C. (1998) J. Phys. Chem. B., 102, 2111–2116.
Ferraro, M.B. (2000) J. Mol. Struct. (Theochem.), 528, 199–209.
Fiebig, K.M., Schwalbe, H., Buck, M., Smith, L.J. and Dobson, C.M. (1996) J. Phys. Chem., 100, 2661–2666.
Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, J.A., Jr., Stratmann, R.E., Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochterski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Cioslowski, J., Ortiz, J.V., Baboul, A.G., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C., Head-Gordon, M., Replogle, E.S., and Pople, J.A. (1998) Gaussian 98, Revision A.7, Inc., Pittsburgh PA.
Gay, D.M., (1983) ACM Trans. Math. Software, 9, 503–524.
Gilson, M.K. (1993) Prot. Struct. Funct. Genet., 15, 266–282.
Gō, N. and Scheraga, H.A. (1969) J. Chem. Phys., 51, 4751–4767.
Havlin, R.H., Le, H., Laws, D.D., deDios, A.C. and Oldfield, E. (1997) J. Am. Chem. Soc., 119, 11951–11958.
Helgaker, T., Jaszuński, M., and Ruud, K. (1999) Chem. Rev., 99, 293–352.
Hennig, M., Bermel, W., Spencer, A., Dobson, C.M., Smith, L.J. and Schwalbe, H. (1999) J. Mol. Biol., 288, 705–723.
Jameson, A.K., and Jameson, C.J. (1987) Chem. Phys. Lett., 134, 461–466.
Jiménez, M.A., Nieto, J.L., Rico, M., Santoro, J., Herranz, J. and Bermejo, F.J. (1986) J. Mol. Struct., 143, 435–438.
Karplus, M. (1959) J. Chem. Phys., 30, 11–15.
Karplus, M. (1963) J. Am. Chem. Soc., 85, 2870–2871.
Kemmink, J., Van Mierlo, C.P.M., Scheek, R.M. and Creighton, T.E. (1993) J. Mol. Biol., 220, 312–322.
Laskowski, Jr. M. and Scheraga, H.A. (1954) J. Am. Chem. Soc., 76, 6305–6319.
Lee, C, Yang, W. and Parr, R.G. (1988) Phys. Rev. B., 37, 785–789.
Merutka, G., Dyson, H.J. and Wright, P.E. (1995) J. Biom. NMR, 5, 14–24.
Momany, F. A., McGuire, R.F., Burgess, A.W. and Scheraga H.A. (1975) J. Phys. Chem., 79, 2361–2381.
Némethy, G., Gibson, K.D., Palmer, K.A., Yoon C.N., Paterlini G., Zagari, A., Rumsey, S. and Scheraga H.A. (1992) J. Phys. Chem., 96, 6472–6484.
Némethy, G., Pottle, M.S. and Scheraga H.A. (1983) J. Phys. Chem., 87, 1883–1887.
Neurath, H. Greenstein, J.P., Putnam, F.W. and Erickson, J.O. (1944) Chem. Revs., 34, 157–265.
O'Connell, T.M., Wang, L., Tropsha, A. and Hermans, J. (1999) Prot. Struct. Funct. Genet., 36, 407–418.
O'Donnell, T.J., Hotovy, S.G., Pottle, M.S., Ripoll, D.R. and Scheraga, H.A. (1996) In Lecture Notes in Computer Science, Vol. 1067: High-Performance Computing and Networking, Liddel, H. Colbrook, A., Hertzberger, B. and Sloot, P., Eds., Springer-Verlag, Berlin, Heidelberg, New York, pp. 365–373.
Ösapay, K. and Case, D.A. (1994) J. Biomol. NMR, 4, 215–230.
Pardi, A., Billeter, M. and Wüthrich, K. (1984) J. Mol. Biol., 180, 741–751.
Pearson, J.G., Le, H., Sanders, L.K., Godbout, N., Havlin, R.H., and Oldfield, E. (1997) J. Am. Chem. Soc., 119, 11941–11950.
Perrin, D.D. (1972) Dissociation Constants of Organic Bases in Aqueous Solution, Butterworths, London.
Ramachandran, G.N., Ramakrishnan, C. and Sasisekharan, V. (1963) J. Mol. Biol., 7, 95–99.
Richarz, R. and Wüthrich, K. (1978) Biopolymers, 17, 2133–2141.
Ripoll, D.R. and Scheraga, H.A. (1988) Biopolymers, 27, 1283–1303.
Ripoll, D.R. and Scheraga, H.A. (1989) J. Protein Chem., 8, 263–287.
Ripoll, D.R., Liwo, A. and Scheraga, H.A. (1998) Biopolymers, 46, 117–126.
Ripoll, D.R., Vorobjev, Y.N., Liwo, A., Vila, J.A. and Scheraga H.A. (1996) J. Mol. Biol., 264, 770–783.
Scheraga, H.A., Vila, J.A. and Ripoll, D.R. (2002) Biophys. Chem., in press.
Schwarzinger, S., Kroon, G.J.A., Foss, T.R., Chung, J., Wright, P.E. and Dyson, H.J. (2001) J. Am. Chem. Soc., 123, 2970–2978.
Serrano, L. (1995) J. Mol. Biol., 254, 322–333.
Simonson, T. and Brünger, A.T. (1994) J. Phys. Chem., 98, 4683–4694.
Sippl, M.J., Némethy, G. and Scheraga, H.A. (1984) J. Phys. Chem., 88, 6231–6233.
Sitkoff, D. and Case, D.A. (1997) J. Am. Chem. Soc., 119, 12262–12273.
Sitkoff, D., Sharp, K.A. and Honig, B. (1994) J. Phys. Chem., 98, 1978–1988.
Smith, L.J., Bolin, K.A., Schwalbe, H., MacArthur, M.W., Thornton, J.M. and Dobson, C.M. (1996) J. Mol. Biol., 255, 494–506.
Sun, H., Sanders, L.K. and Oldfield, E. (2002) J. Am. Chem. Soc., 124, 5486–5495.
Swindells, M.B., MacArthur, M.W. and Thornton, J.M. (1995) Nat. Struct. Biol., 2, 596–603.
Vila, J.A., Ripoll, D.R. and Scheraga, H.A. (2000) Proc. Natl. Acad. Sci. USA, 97, 13075–13079.
Vila, J.A., Ripoll, D.R. and Scheraga, H.A. (2001) Biopolymers, 58, 235–246.
Vila, J.A., Ripoll, D.R., Villegas, M.E., Vorobjev, Y.N. and Scheraga, H.A. (1998) Biophys. J., 75, 2637–2646.
Vorobjev, Y.N. and Scheraga, H.A. (1997) J. Comput. Chem., 18, 569–583.
Vorobjev, Y.N., Scheraga, H.A., Hitz, B. and Honig, B. (1994) J. Phys. Chem., 98, 10940–10948.
Vorobjev, Y.N., Scheraga, H.A. and Honig, B. (1995) J. Phys. Chem., 99, 7180–7187.
Wang, B., Fleischer, U., Hinton, J.F. and Pulay, P. (2001) J. Comp. Chem., 22, 1887–1895.
West, N.J. and Smith, L.J. (1998) J. Mol. Biol., 280, 867–877.
Williamson, P.M., Asakura, T., Nakamura, E. and Demura, M. (1992) J. Biomol. NMR, 2, 93–98.
Wishart, D.S. and Case, D.A. (2001) Meth. Enzymol., 338, 3–34.
Wishart, D.S. and Nip, A.M. (1998) Biochem. Cell Biol., 76153–163.
Wishart, D.S., Sykes, B.D. and Richards, F.M. (1991) J. Mol. Biol., 222, 311–333.
Wolinski, K., Hinton, J.F. and Pulay, P. (1990) J. Am. Chem. Soc., 112, 8251–8260.
Wüthrich, K. (1986) NMR of Proteins and Nucleic Acids, John Wiley and Sons, New York, NY, p. 17.
Xu, X.-P. and Case, D.A. (2001) J. Biomol. NMR, 21, 321–333.
Yang, A.-S. and Honig, B. (1993) J. Mol. Biol., 231, 459–474.
Yang, A.-S., Gunner, M.R., Sampogna, R., Sharp, K. and Honig, B. (1993) Prot. Struct. Funct. Genet., 15, 252–265.
Zimmerman, S.S., Pottle, M.S., Némethy, G. and Scheraga, H.A. (1977) Macromolecules, 10, 1–9.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Vila, J.A., Ripoll, D.R., Baldoni, H.A. et al. Unblocked statistical-coil tetrapeptides and pentapeptides in aqueous solution: A theoretical study. J Biomol NMR 24, 245–262 (2002). https://doi.org/10.1023/A:1021633403715
Issue Date:
DOI: https://doi.org/10.1023/A:1021633403715