The Many Faces of Structure-Based Potentials: From Protein Folding Landscapes to Structural Characterization of Complex Biomolecules

Chapter
Part of the Biological and Medical Physics, Biomedical Engineering book series (BIOMEDICAL)

Abstract

Structural biology techniques, such as nuclear magnetic resonance (NMR), x-ray crystallography, and cryogenic electron microscopy (cryo-EM), have provided extraordinary insights into the details of the functional configurations of biomolecular systems. Recent advances in x-ray crystallography and cryo-EM have allowed for structural characterization of large molecular machines such as the ribosome, proteasome, and spliceosome. This deluge of structural data has been complemented by experimental techniques capable of probing dynamic information, such as Förster resonance energy transfer (FRET) and stopped flow spectrometry. While these experimental studies have provided tremendous insights into the dynamics of biomolecular systems, it is often difficult to combine the low resolution dynamical data with the high-resolution structural data into a consistent picture. Computer simulation of these biomolecular systems bridges static structural data with dynamic experiments at atomic resolution (Fig. 1).

Keywords

Energy Landscape Free Energy Barrier Free Energy Landscape Native Contact Biomolecular System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

JKN would like to thank Joanna Sułkowska for many helpful discussions and Paul Whitford and Ryan Hayes for a careful reading of the chapter. This work was supported by the Center for Theoretical Biological Physics sponsored by the national science foundation (NSF) (Grant PHY-0822283) and NSF Grant NSF-MCB-1051438.

References

  1. 1.
    Adcock, S.A., McCammon, J.A.: Molecular dynamics: survey of methods for simulating the activity of proteins. Chem. Rev. 106(5), 1589–1615 (2006)CrossRefGoogle Scholar
  2. 2.
    Andrews, B.T., Gosavi, S., Finke, J.M., Onuchic, J.N., Jennings, P.A.: The dual-basin landscape in gfp folding. Proc. Nat. Acad. Sci. USA 105(34), 12283–12288 (2008)ADSCrossRefGoogle Scholar
  3. 3.
    de Araujo, A.F.P., Onuchic, J.N.: A sequence-compatible amount of native burial information is sufficient for determining the structure of small globular proteins. Proc. Nat. Acad. Sci. USA 106(45), 19001–19004 (2009)ADSCrossRefGoogle Scholar
  4. 4.
    Azia, A., Levy, Y.: Nonnative electrostatic interactions can modulate protein folding: molecular dynamics with a grain of salt. J. Mol. Biol. 393(2), 527–542 (2009)CrossRefGoogle Scholar
  5. 5.
    Baker, D.: A surprising simplicity to protein folding. Nature 405(6782), 39–42 (2000)ADSCrossRefGoogle Scholar
  6. 6.
    Baxter, E.L., Jennings, P.A., Onuchic, J.N.: Interdomain communication revealed in the diabetes drug target mitoneet. Proc. Nat. Acad. Sci. USA 108(13), 5266–5271 (2011)ADSCrossRefGoogle Scholar
  7. 7.
    Bowers, K.J., Chow, E., Xu, H., Dror, R.O., Eastwood, M.P., Gregersen, B.A., Klepeis, J.L., Kolossvary, I., Moraes, M.A., Sacerdoti, F.D., Salmon, J.K., Shan, Y., Shaw, D.E.: Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of ACM/IEEE, p. 43 (2006)Google Scholar
  8. 8.
    Bryngelson, J., Wolynes, P.: Spin glasses and the statistical mechanics of protein folding. Proc. Nat. Acad. Sci. USA 84, 7524 (1987)ADSCrossRefGoogle Scholar
  9. 9.
    Bryngelson, J., Wolynes, P.: Intermediates and barrier crossing in a random energy model (with applications to protein folding). J. Phys. Chem. 93, 6902–6915 (1989)CrossRefGoogle Scholar
  10. 10.
    Bryngelson, J.D., Onuchic, J.N., Socci, N.D., Wolynes, P.G.: Funnels, pathways, and the energy landscape of protein folding: a synthesis. Proteins: Struct. Funct. Bioinf. 21(3), 167–195 (1995)CrossRefGoogle Scholar
  11. 11.
    Chavez, L.L., Onuchic, J.N., Clementi, C.: Quantifying the roughness on the free energy landscape: entropic bottlenecks and protein folding rates. J. Am. Chem. Soc. 126(27), 8426–8432 (2004)CrossRefGoogle Scholar
  12. 12.
    Cheung, M.S., García, A.E., Onuchic, J.N.: Protein folding mediated by solvation: water expulsion and formation of the hydrophobic core occur after the structural collapse. Proc. Nat. Acad. Sci. USA 99(2), 685–690 (2002)ADSCrossRefGoogle Scholar
  13. 13.
    Cho, S., Levy, Y., Wolynes, P.G.: P versus Q: Structural reaction coordinates capture protein folding on smooth landscapes. Proc. Nat. Acad. Sci. USA 103(3), 586–591 (2006)ADSCrossRefGoogle Scholar
  14. 14.
    Cho, S.S., Weinkam, P., Wolynes, P.G.: Origins of barriers and barrierless folding in bbl. Proc. Nat. Acad. Sci. USA 105(1), 118–123 (2008)ADSCrossRefGoogle Scholar
  15. 15.
    Clementi, C., Nymeyer, H., Onuchic, J.N.: Topological and energetic factors: what determines the structural details of the transition state ensemble and “en-route” intermediates for protein folding? An investigation for small globular proteins. J. Mol. Biol. 298(5), 937–953 (2000)Google Scholar
  16. 16.
    Clementi, C., García, A.E., Onuchic, J.N.: Interplay among tertiary contacts, secondary structure formation and side-chain packing in the protein folding mechanism: all-atom representation study of protein l. J. Mol. Biol. 326(3), 933–954 (2003)CrossRefGoogle Scholar
  17. 17.
    Clementi, C., Plotkin, S.S.: The effects of nonnative interactions on protein folding rates: theory and simulation. Protein Sci. 13(7), 1750–1766 (2004)CrossRefGoogle Scholar
  18. 18.
    Ferguson, N., Schartau, P.J., Sharpe, T.D., Sato, S., Fersht, A.R.: One-state downhill versus conventional protein folding. J. Mol. Biol. 344(2), 295–301 (2004)CrossRefGoogle Scholar
  19. 19.
    Fersht, A.R.: Characterizing transition-states in protein-folding - an essential step in the puzzle. Curr. Opin. Struct. Biol. 5(1), 79–84 (1995)CrossRefGoogle Scholar
  20. 20.
    Frauenfelder, H., Sligar, S.G., Wolynes, P.G.: The energy landscapes and motions of proteins. Science 254(5038), 1598–1603 (1991)ADSCrossRefGoogle Scholar
  21. 21.
    Gambin, Y., Schug, A., Lemke, E.A., Lavinder, J.J., Ferreon, A.C.M., Magliery, T.J., Onuchic, J.N., Deniz, A.A.: Direct single-molecule observation of a protein living in two opposed native structures. Proc. Nat. Acad. Sci. USA 106(25), 10153–10158 (2009)ADSCrossRefGoogle Scholar
  22. 22.
    Gosavi, S., Chavez, L.L., Jennings, P.A., Onuchic, J.N.: Topological frustration and the folding of interleukin-1 beta. J. Mol. Biol. 357(3), 986–996 (2006)CrossRefGoogle Scholar
  23. 23.
    Hess, B., Kutzner, C., van der Spoel, D., Lindahl, E.: Gromacs 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theo. Comput. 4(3), 435–447 (2008)CrossRefGoogle Scholar
  24. 24.
    Hyeon, C., Jennings, P.A., Adams, J.A., Onuchic, J.N.: Ligand-induced global transitions in the catalytic domain of protein kinase A. Proc. Nat. Acad. Sci. USA 106(9), 3023–3028 (2009)ADSCrossRefGoogle Scholar
  25. 25.
    Hyeon, C., Onuchic, J.N.: Mechanical control of the directional stepping dynamics of the kinesin motor. Proc. Nat. Acad. Sci. USA 104(44), 17382–17387 (2007)ADSCrossRefGoogle Scholar
  26. 26.
    Okazaki, K., Koga, N., Takada, S., Onuchic, J.N., Wolynes, P.G.: Multiple-basin energy landscapes for large-amplitude conformational motions of proteins: struc-based molecular dynamics simulations. Proc. Nat. Acad. Sci. USA 103(32), 11844–11849 (2006)ADSCrossRefGoogle Scholar
  27. 27.
    Jamros, M.A., Oliveira, L.C., Whitford, P.C., Onuchic, J.N., Adams, J.A., Blumenthal, D.K., Jennings, P.A.: Proteins at work: a combined small angle x-ray scattering and theoretical determination of the multiple structures involved on the protein kinase functional landscape. J. Biol. Chem. 285(46), 36121–36128 (2010)CrossRefGoogle Scholar
  28. 28.
    Kaya, H., Chan, H.S.: Solvation effects and driving forces for protein thermodynamic and kinetic cooperativity: how adequate is native-centric topological modeling? J. Mol. Biol. 326(3), 911–931 (2003)CrossRefGoogle Scholar
  29. 29.
    Koga, N., Takada, S.: Roles of native topology and chain-length scaling in protein folding: a simulation study with a go-like model. J. Mol. Biol. 313(1), 171–180 (2001)CrossRefGoogle Scholar
  30. 30.
    Kouza, M., Li, M.S., O’brien, E.P., Hu, C.-K., Thirumalai, D.: Effect of finite size on cooperativity and rates of protein folding. J. Phys. Chem. A 110(2), 671–676 (2006)CrossRefGoogle Scholar
  31. 31.
    Kumar, S., Rosenberg, J., Bouzida, D., Swendsen, R.H.: The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J. Comput. Chem. 13(8), 1011 (1992)Google Scholar
  32. 32.
    Lammert, H., Schug, A., Onuchic, J.N.: Robustness and generalization of structure-based models for protein folding and function. Proteins: Struct. Funct. Bioinf. 77(4), 881–891 (2009)CrossRefGoogle Scholar
  33. 33.
    Leopold, P.E., Montal, M., Onuchic, J.N.: Protein folding funnels - a kinetic approach to the sequence structure relationship. Proc. Nat. Acad. Sci. USA 89(18), 8721–8725 (1992)ADSCrossRefGoogle Scholar
  34. 34.
    Levy, Y., Cho, S.S., Shen, T., Onuchic, J.N., Wolynes, P.G.: Symmetry and frustration in protein energy landscapes: a near degeneracy resolves the rop dimer-folding mystery. Proc. Nat. Acad. Sci. USA 102(7), 2373–2378 (2005)ADSCrossRefGoogle Scholar
  35. 35.
    Levy, Y., Onuchic, J.N., Wolynes, P.G.: Fly-casting in protein-dna binding: frustration between protein folding and electrostatics facilitates target recognition. J. Am. Chem. Soc. 129(4), 738–739 (2007)CrossRefGoogle Scholar
  36. 36.
    Levy, Y., Wolynes, P.G., Onuchic, J.N.: Protein topology determines binding mechanism. Proc. Nat. Acad. Sci. USA 101(2), 511–516 (2004)ADSCrossRefGoogle Scholar
  37. 37.
    Lindorff-Larsen, K., Piana, S., Dror, R.O., Shaw, D.E.: How fast-folding proteins fold. Science 334, 517–520 (2011)Google Scholar
  38. 38.
    McCammon, J.A., Gelin, B.R., Karplus, M.: Dynamics of folded proteins. Nature 267(5612), 585–590 (1977)Google Scholar
  39. 39.
    Mittal, A., Jayaram, B.: Backbones of folded proteins reveal novel invariant amino acid neighborhoods. J. Biomol. Struct. Dyn. 28(4), 443–454 (2011)Google Scholar
  40. 40.
    Miyashita, O., Onuchic, J.N., Wolynes, P.G.: Nonlinear elasticity, proteinquakes, and the energy landscapes of functional transitions in proteins. Proc. Nat. Acad. Sci. USA 100(22), 12570–12575 (2003)ADSCrossRefGoogle Scholar
  41. 41.
    Mor, A., Ziv, G., Levy, Y.: Simulations of proteins with inhomogeneous degrees of freedom: the effect of thermostats. J. Comput. Chem. 29(12), 1992–1998 (2008)CrossRefGoogle Scholar
  42. 42.
    Nechushtai, R., Lammert, H., Michaeli, D., Eisenberg-Domovich, Y., Zuris, J.A., Luca, M.A., Capraro, D.T., Fish, A., Shimshon, O., Roy, M., Schug, A., Whitford, P.C., Livnah, O., Onuchic, J.N., Jennings, P.A.: Allostery in the ferredoxin protein motif does not involve a conformational switch. Proc. Nat. Acad. Sci. USA 108(6), 2240–2245 (2011)ADSCrossRefGoogle Scholar
  43. 43.
    Noel, J.K., Sulkowska, J.I., Onuchic, J.N.: Slipknotting upon native-like loop formation in a trefoil knot protein. Proc. Nat. Acad. Sci. USA 107(35), 15403–15408 (2010)ADSCrossRefGoogle Scholar
  44. 44.
    Noel, J.K., Whitford, P.C., Sanbonmatsu, K.Y., Onuchic, J.N.: Smog@ctbp: simplified deployment of structure-based models in gromacs. Nucleic Acids Res. 38, W657 (2010)CrossRefGoogle Scholar
  45. 45.
    Nymeyer, H., García, A.E., Onuchic, J.N.: Folding funnels and frustration in off-lattice minimalist protein landscapes. Proc. Nat. Acad. Sci. USA 95(11), 5921–5928 (1998)ADSCrossRefGoogle Scholar
  46. 46.
    Oliveira, R.J., Whitford, P.C., Chahine, J., Wang, J., Onuchic, J.N., Leite, V.B.P.: The origin of nonmonotonic complex behavior and the effects of nonnative interactions on the diffusive properties of protein folding. Biophys. J. 99(2), 600–608 (2010)ADSCrossRefGoogle Scholar
  47. 47.
    Onuchic, J.N., Wolynes, P.G.: Theory of protein folding. Curr. Opin. Struct. Biol. 14(1), 70–75 (2004)CrossRefGoogle Scholar
  48. 48.
    Orzechowski, M., Tama, F.: Flexible fitting of high-resolution x-ray structures into cryoelectron microscopy maps using biased molecular dynamics simulations. Biophys. J. 95(12), 5692–5705 (2008)ADSCrossRefGoogle Scholar
  49. 49.
    Phillips, J.C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot, C., Skeel, R.D., Kalé, L., Schulten, K.: Scalable molecular dynamics with namd. J. Comput. Chem. 26(16), 1781–1802 (2005)CrossRefGoogle Scholar
  50. 50.
    Ratje, A.H., Loerke, J., Mikolajka, A., Brünner, M., Hildebrand, P.W., Starosta, A.L., Dönhöfer, A., Connell, S.R., Fucini, P., Mielke, T., Whitford, P.C., Onuchic, J.N., Yu, Y., Sanbonmatsu, K.Y., Hartmann, R.K., Penczek, P.A., Wilson, D.N., Spahn, C.M.T.: Head swivel on the ribosome facilitates translocation by means of intra-subunit trna hybrid sites. Nature 468(7324), 713–716 (2010)ADSCrossRefGoogle Scholar
  51. 51.
    Schug, A., Weigt, M., Onuchic, J.N., Hwa, T., Szurmant, H.: High-resolution protein complexes from integrating genomic information with molecular simulation. Proc. Nat. Acad. Sci. USA 106(52), 22124–22129 (2009)ADSCrossRefGoogle Scholar
  52. 52.
    Schug, A., Whitford, P.C., Levy, Y., Onuchic, J.N.: Mutations as trapdoors to two competing native conformations of the rop-dimer. Proc. Nat. Acad. Sci. USA 104(45), 17674–17679 (2007)ADSCrossRefGoogle Scholar
  53. 53.
    Scott, K.A., Batey, S., Hooton, K.A., Clarke, J.: The folding of spectrin domains i: wild-type domains have the same stability but very different kinetic properties. J. Mol. Biol. 344(1), 195–205 (2004)CrossRefGoogle Scholar
  54. 54.
    Shaw, D.E., Maragakis, P., Lindorff-Larsen, K., Piana, S., Dror, R.O., Eastwood, M.P., Bank, J.A., Jumper, J.M., Salmon, J.K., Shan, Y., Wriggers, W.: Atomic-level characterization of the structural dynamics of proteins. Science 330(6002), 341–346 (2010)ADSCrossRefGoogle Scholar
  55. 55.
    Sobolev, V., Sorokine, A., Prilusky, J., Abola, E.E., Edelman, M.: Automated analysis of interatomic contacts in proteins. Bioinformatics 15(4), 327–332 (1999)CrossRefGoogle Scholar
  56. 56.
    Socci, N.D., Onuchic, J.N., Wolynes, P.G.: Diffusive dynamics of the reaction coordinate for protein folding funnels. J. Chem. Phys. 104(15), 5860–5868 (1996)ADSCrossRefGoogle Scholar
  57. 57.
    Sułkowska, J., Sułkowski, P., Szymczak, P., Cieplak, M.: Tightening of knots in proteins. Phys. Rev. Lett. 100(5), 058106 (2008)ADSCrossRefGoogle Scholar
  58. 58.
    Sułkowska, J.I., Cieplak, M.: Selection of optimal variants of gō-like models of proteins through studies of stretching. Biophys. J. 95(7), 3174–3191 (2008)ADSCrossRefGoogle Scholar
  59. 59.
    Sułkowska, J.I., Sułkowski, P., Onuchic, J.: Dodging the crisis of folding proteins with knots. Proc. Nat. Acad. Sci. USA 106(9), 3119–3124 (2009)ADSMATHCrossRefGoogle Scholar
  60. 60.
    Sutto, L., Lätzer, J., Hegler, J.A., Ferreiro, D.U., Wolynes, P.G.: Consequences of localized frustration for the folding mechanism of the im7 protein. Proc. Nat. Acad. Sci. USA 104(50), 19825–19830 (2007)ADSCrossRefGoogle Scholar
  61. 61.
    Tirion, M.: Large amplitude elastic motions in proteins from a single-parameter, atomic analysis. Phys. Rev. Lett. 77(9), 1905–1908 (1996)ADSCrossRefGoogle Scholar
  62. 62.
    Veitshans, T., Klimov, D., Thirumalai, D.: Protein folding kinetics: timescales, pathways and energy landscapes in terms of sequence-dependent properties. Folding and Design 2(1), 1–22 (1997)CrossRefGoogle Scholar
  63. 63.
    Wales, D.J.: Energy Landscapes. Cambridge University Press, Cambridge (2003)Google Scholar
  64. 64.
    Whitford, P., Schug, A., Saunders, J., Hennelly, S., Onuchic, J., Sanbonmatsu, K.: Supplementary-nonlocal helix formation is key to understanding s-adenosylmethionine-1 riboswitch function. Biophys. J. 96(2), L7–L9 (2009)CrossRefGoogle Scholar
  65. 65.
    Whitford, P.C., Ahmed, A., Yu, Y., Hennelly, S.P., Tama, F., Spahn, C.M.T., Onuchic, J., Sanbonmatsu, K.Y.: Excited states of ribosome translocation revealed through integrative molecular modeling. Proc. Nat. Acad. Sci. USA 108(47), 18943–18948 (2011)CrossRefGoogle Scholar
  66. 66.
    Whitford, P.C., Geggier, P., Altman, R.B., Blanchard, S.C., Onuchic, J.N., Sanbonmatsu, K.Y.: Accommodation of aminoacyl-trna into the ribosome involves reversible excursions along multiple pathways. RNA 16(6), 1196–1204 (2010)CrossRefGoogle Scholar
  67. 67.
    Whitford, P.C., Gosavi, S., Onuchic, J.N.: Conformational transitions in adenylate kinase. Allosteric communication reduces misligation. J. Biol. Chem. 283(4), 2042–2048 (2008)Google Scholar
  68. 68.
    Whitford, P.C., Miyashita, O., Levy, Y., Onuchic, J.N.: Conformational transitions of adenylate kinase: switching by cracking. J. Mol. Biol. 366(5), 1661–1671 (2007)CrossRefGoogle Scholar
  69. 69.
    Whitford, P.C., Noel, J.K., Gosavi, S., Schug, A., Sanbonmatsu, K.Y., Onuchic, J.N.: An all-atom structure-based potential for proteins: bridging minimal models with all-atom empirical forcefields. Proteins: Struct. Funct. Bioinf. 75(2), 430–441 (2009)CrossRefGoogle Scholar
  70. 70.
    Wodak, S.J., Janin, J.: Structural basis of macromolecular recognition. Adv. Protein Chem. 61, 9–73 (2002)CrossRefGoogle Scholar
  71. 71.
    Wu, L., Zhang, J., Qin, M., Liu, F., Wang, W.: Folding of proteins with an all-atom go-model. J. Chem. Phys. 128(23), 235103 (2008)ADSCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Physics and Center for Theoretical Biological PhysicsUniversity of CaliforniaLa JollaUSA
  2. 2.Department of Physics and Center for Theoretical Biological PhysicsRice UniversityHoustonUSA

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