A Stereochemically-Bent β-Hairpin: Scrutiny of Folding by Comparing a Heteropolypeptide and Cognate Oligoalanine

DOI: 10.4236/ojpc.2014.43012   PDF   HTML   XML   2,210 Downloads   2,645 Views  


A poly-L β-hairpin bent stereochemically as a boat-shaped protein of mixed-L,D structure is scrutinized in basis of ordering as minimum of energy specific for its sequenceand solvent. The model suitable for the scrutiny is accomplished by design. A terminally-blocked oligoalanine is nucleated overDPro6-Gly7 and DPro6-LAsp7 dipeptide structures as a twelve-residue β-hairpin and bent stereochemically as a boat-shaped fold. The structure is inverse designed with side chains suitable to bind substrate p-nitophenyl phosphate, a surrogate substrate of acetyl choline and CO2. The designed sequences were proven by spectroscopy and molecular dynamics to order with solvent effects of water and display high binding affinity for the substrate. One of the proteins and a cognate oligoalanine are evolved with molecular dynamics to equilibrium in a solvent bath of water. Molecular dynamics studies establish that heteropolypeptide well ordered as β-hairpin fold and cognate oligoalanine as an ensemble of hairpin-like folds in water. The ordering of cognate oligoalanine as ensembles of hairpin-like folds manifests combined role of water as strong dielectric and weak dipolar solvent of peptides. The roles of stereochemistry and chemical details of sequence in defining polypeptides as energy minima under specific effect of solvent are illuminated and have been discussed.

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Srivastava, K. and Durani, S. (2014) A Stereochemically-Bent β-Hairpin: Scrutiny of Folding by Comparing a Heteropolypeptide and Cognate Oligoalanine. Open Journal of Physical Chemistry, 4, 81-97. doi: 10.4236/ojpc.2014.43012.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Dill, K.A., Ozkan, S.B., Shell, M.S. and Weikl, T.R. (2008) The Protein Folding Problem. Annual Review of Biophysics, 37, 289-316. http://dx.doi.org/10.1146/annurev.biophys.37.092707.153558
[2] Onuchic, J.N. and Wolynes, P.G. (2004) Theory of Protein Folding. Current Opinion in Structural Biology, 14, 70-75. http://dx.doi.org/10.1016/j.sbi.2004.01.009
[3] Daggett, V. and Fersht, A. (2003) The Present View of the Mechanism of Protein Folding. Nature Reviews Molecular Cell Biology, 4, 497-502. http://dx.doi.org/10.1038/nrm1126
[4] Dannenberg, J.J. (2005) The Importance of Cooperative Interactions and a Solid-State Paradigm to Proteins: What Peptide Chemists Can Learn from Molecular Crystals. Advances in Protein Chemistry, 72, 227-273. http://dx.doi.org/10.1016/S0065-3233(05)72009-X
[5] Hua, S., Xu, L., Li, W. and Li, S. (2011) Cooperativity in Long Alpha- and 3(10)-Helical Polyalanines: Both Electrostatic and van der Waals Interactions Are Essential. Journal of Physical Chemistry B, 115, 11462-11469. http://dx.doi.org/10.1021/jp203423w
[6] Elstner, M., Jalkanen, K.J., Knapp-Mohammady, M., Frauenheim, T. and Suhai, S. (2000) DFT Studies on Helix Formation in N-Acetyl-(L-Alanyl)n-N’-Methylamide for n = 1 - 20. Chemical Physics, 256, 15-27. http://dx.doi.org/10.1016/S0301-0104(00)00100-2
[7] Rossi, M., Blum, V., Kupser, P., von Helden, G., Bierau, F., Pagel, K., Meijer, G. and Scheffler, M. (2010) Secondary Structure of Ac-Alan-LysH+ Polyalanine Peptides (n = 5, 10, 15) in Vacuo: Helical or Not? Journal of Physical Chemistry Letters, 1, 3465-3470. http://dx.doi.org/10.1021/jz101394u
[8] Salvador, P., Asensio, A. and Dannenberg, J.J. (2007) The Effect of Aqueous Solvation upon Alpha-Helix Formation for Polyalanines. Journal of Physical Chemistry B, 111, 7462-7466.
[9] Topol, I.A., Burt, S.K., Deretey, E., Tang, T.H., Perczel, A., Rashin, A. and Csizmadia, I.G. (2001) Alpha- and 3(10)-Helix Interconversion: A Quantum-Chemical Study on Polyalanine Systems in the Gas Phase and in Aqueous Solvent. Journal of the American Chemical Society, 123, 6054-6060.
[10] Tsai, M.I., Xu, Y. and Dannenberg, J.J. (2005) Completely Geometrically Optimized DFT/ONIOM Triple-Helical Collagen-Like Structures Containing the ProProGly, ProProAla, ProProDAla, and ProProDSer Triads. Journal of the American Chemical Society, 127, 14130-14131.
[11] Tsai, M.I., Xu, Y. and Dannenberg, J.J. (2009) Ramachandran Revisited. DFT Energy Surfaces of Diastereomeric Trialanine Peptides in the Gas Phase and Aqueous Solution. Journal of Physical Chemistry B, 113, 309-318. http://dx.doi.org/10.1021/jp8063646
[12] Tsemekhman, K., Goldschmidt, L., Eisenberg, D. and Baker, D. (2007) Cooperative Hydrogen Bonding in Amyloid Formation. Protein Science, 16, 761-764. http://dx.doi.org/10.1110/ps.062609607
[13] Han, W.G., Jalkanen, K.J., Elstner, M. and Suhai, S. (1998) Theoratical Study of Aqueous N-Acetyl-L-Alanine N’-Methyl amide: Structure and Raman, VCD, and ROA Spectra. Journal of Physical Chemistry B, 102, 2587-2602. http://dx.doi.org/10.1021/jp972299m
[14] Wieczorek, R. and Dannenberg, J.J. (2005) Enthalpies of Hydrogen-Bonds in Alpha-Helical Peptides. An ONIOM DFT/AM1 Study. Journal of the American Chemical Society, 127, 14534-14535.
[15] Brooks, B.R., Brooks III, C.L., Mackerell Jr., A.D., Nilsson, L., Petrella, R.J., Roux, B., Won, Y., Archontis, G., Bartels, C., Boresch, S., Caflisch, A., Caves, L., Cui, Q., Dinner, A.R., Feig, M., Fischer, S., Gao, J., Hodoscek, M., Im, W., Kuczera, K., Lazaridis, T., Ma, J., Ovchinnikov, V., Paci, E., Pastor, R.W., Post, C.B., Pu, J.Z., Schaefer, M., Tidor, B., Venable, R.M., Woodcock, H.L., Wu, X., Yang, W., York, D.M. and Karplus, M. (2009) CHARMM: The Bio-molecular Simulation Program. Journal of Computational Chemistry, 30, 1545-1614. http://dx.doi.org/10.1002/jcc.21287
[16] Guvench, O. and MacKerell Jr., A.D. (2008) Comparison of Protein Force Fields for Molecular Dynamics Simulations. Molecular Modeling of Proteins, 443, 63-88. http://dx.doi.org/10.1007/978-1-59745-177-2_4
[17] van Gunsteren, W.F., Dolenc, J. and Mark, A.E. (2008) Molecular Simulation as an Aid to Experimentalists. Current Opinion in Structural Biology, 18, 149-153.
[18] Wang, D., Friedmann, M., Gattin, Z., Jaun, B. and van Gunsteren, W.F. (2010) The Propensity of α-Aminoisobutyric Acid (=2-Methylalanine; Aib) to Induce Helical Secondary Structure in an α-Heptapeptide: A Computational Study. Helvetica Chimica Acta, 93, 1513-1531.
[19] Yu, H., Ramseier, M., Burgi, R. and van Gunsteren, W.F. (2004) Comparison of Properties of Aib-Rich Peptides in Crystal and Solution: A Molecular Dynamics Study. ChemPhysChem, 5, 633-641.
[20] Zagrovic, B., Lipfert, J., Sorin, E.J., Millett, I.S., van Gunsteren, W.F., Doniach, S. and Pande, V.S. (2005) Unusual Compactness of a Polyproline Type II Structure. Proceedings of the National Academy of Sciences of the United States of America, 102, 11698-11703.
[21] Brooks III, C.L. (2002) Protein and Peptide Folding Explored with Molecular Simulations. Accounts of Chemical Research, 35, 447-454. http://dx.doi.org/10.1021/ar0100172
[22] Shea, J.E. and Brooks III, C.L. (2001) From Folding Theories to Folding Proteins: A Review and Assessment of Simulation Studies of Protein Folding and Unfolding. Annual Review of Physical Chemistry, 52, 499-535. http://dx.doi.org/10.1146/annurev.physchem.52.1.499
[23] Karanicolas, J. and Brooks III, C.L. (2004) An Evolution of Minimalist Models for Protein Folding: From the Behavior of Protein-Like Polymers to Protein Function. Biosilico, 2, 127-133.
[24] Chakrabartty, A. and Baldwin, R.L. (1995) Stability of α-Helices. Advances in Protein Chemistry, 46, 141-176. http://dx.doi.org/10.1016/S0065-3233(08)60334-4
[25] Head-Gordon, T., Stillinger, F.H., Wright, M.H. and Gay, D.M. (1992) Poly(L-Alanine) as a Universal Reference Material for Understanding Protein Energies and Structures. Proceedings of the National Academy of Sciences of the United States of America, 89, 11513-11517.
[26] Makowska, J., Liwo, A., ?mudzińska, W., Lewandowska, A., Chmurzynski, L. and Scheraga, H.A. (2012) Like-Charged Residues at the Ends of Oligoalanine Sequences Might Induce a Chain Reversal. Biopolymers, 97, 240-249. http://dx.doi.org/10.1002/bip.22013
[27] Makowska, J., Rodziewicz-Motowidlo, S., Baginska, K., Makowski, M., Vila, J.A., Liwo, A., Chmurzynski, L. and Scheraga, H.A. (2007) Further Evidence for the Absence of Polyproline II Stretch in the XAO Peptide. Biophysical Journal, 92, 2904-2917. http://dx.doi.org/10.1529/biophysj.106.097550
[28] Pappu, R.V., Srinivasan, R. and Rose, G.D. (2000) The Flory Isolated-Pair Hypothesis Is Not Valid for Polypeptide Chains: Implications for Protein Folding. Proceedings of the National Academy of Sciences of the United States of America, 97, 12565-12570.
[29] Ramakrishnan, V., Ranbhor, R. and Durani, S. (2004) Existence of Specific “Folds” in Polyproline II Ensembles of an “Unfolded” Alanine Peptide Detected by Molecular Dynamics. Journal of the American Chemical Society, 126, 16332-16333. http://dx.doi.org/10.1021/ja045787y
[30] Shi, Z., Olson, C.A., Rose, G.D., Baldwin, R.L. and Kallenbach, N.R. (2002) Polyproline II Structure in a Sequence of Seven Alanine Residues. Proceedings of the National Academy of Sciences of the United States of America, 99, 9190-9195. http://dx.doi.org/10.1073/pnas.112193999
[31] Shi, Z., Woody, R.W. and Kallenbach, N.R. (2002) Is Polyproline II a Major Backbone Conformation in Unfolded Proteins? Advances in Protein Chemistry, 62, 163-240. http://dx.doi.org/10.1016/S0065-3233(02)62008-X
[32] Cheng, R.P., Girinath, P., Suzuki, Y., Kuo, H.T., Hsu, H.C., Wang, W.R., Yang, P.A., Gullickson, D., Wu, C.H., Koyack, M.J., Chiu, H.P., Weng, Y.J., Hart, P., Kokona, B., Fairman, R., Lin, T.E. and Barrett, O. (2010) Positional Effects on Helical Ala-Based Peptides. Biochemistry, 49, 9372-9384.
[33] Wieczorek, R. and Dannenberg, J.J. (2003) Hydrogen-Bond Cooperativity, Vibrational Coupling, and Dependence of Helix Stability on Changes in Amino Acid Sequence in Small 310-Helical Peptides. A Density Functional Theory Study. Journal of the American Chemical Society, 125, 14065-14071. http://dx.doi.org/10.1021/ja034034t
[34] Brant, D.A., Miller, W.G. and Flory, P.J. (1967) Conformational Energy Estimates for Statistically Coiling Polypeptide Chains. Journal of Molecular Biology, 23, 47-65.
[35] Flory, P.J. and Schimmel, P.R. (1967) Dipole Moments in Relation to Configuration of Polypeptide Chains. Journal of the American Chemical Society, 89, 6807-6813.
[36] Flory, P.J. (1969) Statistical Mechanics of Chain Molecules. InterScience Publishers, New York.
[37] Kumar, A., Ramakrishnan, V., Ranbhor, R., Patel, K. and Durani, S. (2009) Homochiral Stereochemistry: The Missing Link of Structure to Energetics in Protein Folding. The Journal of Physical Chemistry B, 113, 16435-16442. http://dx.doi.org/10.1021/jp906811k
[38] Ramakrishnan, V., Ranbhor, R., Kumar, A. and Durani, S. (2006) The Link between Sequence and Conformation in Protein Structures Appears to Be Stereochemically Established. The Journal of Physical Chemistry B, 110, 9314-9323. http://dx.doi.org/10.1021/jp056417e
[39] Srivastava, K.R., Kumar, A., Goyal, B. and Durani, S. (2011) Stereochemistry and Solvent Role in Protein Folding: Nuclear Magnetic Resonance and Molecular Dynamics Studies of Poly-L and Alternating-L,D Homopolypeptides in Dimethyl Sulfoxide. The Journal of Physical Chemistry B, 115, 6700-6708.
[40] Durani, S. (2008) Protein Design with L- and D-Alpha-Amino Acid Structures as the Alphabet. Accounts of Chemical Research, 41, 1301-1308. http://dx.doi.org/10.1021/ar700265t
[41] Daura, X., van Gunsteren, W.F. and Mark, A.E. (1999) Folding-Unfolding Thermodynamics of a Beta-Heptapeptide from Equilibrium Simulations. Proteins: Structure, Function, and Bioinformatics, 34, 269-280. http://dx.doi.org/10.1002/(SICI)1097-0134(19990215)34:3<269::AID-PROT1>3.0.CO;2-3
[42] Lindahl, E., Hess, B. and van der Spoel, D. (2001) GROMACS 3.0: A Package for Molecular Simulation and Trajectory Analysis. Journal of Molecular Modeling, 7, 306-317.
[43] Van Gunsteren, W.F., Billeter, S.R., Eising, A.A., Hünenberger, P.H., Krüger, P., Mark, A.E., Scott, W.R.P. and Tironi, I.G. (1996) Biomolecular Simulation: The GROMOS96 Manual and User Guide. Hochschulverlag AG an der ETH Zürich, Zürich.
[44] Ryckaert, J., Ciccotti, G. and Berendsen, H. (1977) Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes. Journal of Computational Physics, 23, 327-341. http://dx.doi.org/10.1016/0021-9991(77)90098-5
[45] Darden, T., York, D. and Pedersen, L. (1993) Particle Mesh Ewald: An N-Log(N) Method for Ewald Sums in Large Systems. The Journal of Chemical Physics, 98, 10089-10092.
[46] Essmann, U., Perera, L., Berkowitz, M.L., Darden, T., Lee, H. and Pedersen, L.G. (1995) A Smooth Particle Mesh Ewald Method. The Journal of Chemical Physics, 103, 8577-8593.
[47] Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K. and Olson, A.J. (1998) Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function. Journal of Computational Chemistry, 19, 1639-1662.
[48] Chan, W.C. and White, P.D. (1989) Fmoc Solid Phase Peptide Synthesis: A Practical Approach. IRL Press, Oxford.

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