Denatured proteins and early folding intermediates simulated in a reduced conformational space
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Conformations of globular proteins in the denatured state were studied using a high-resolution lattice model of proteins and Monte Carlo dynamics. The model assumes a united-atom and high-coordination lattice representation of the polypeptide conformational space. The force field of the model mimics the short-range protein-like conformational stiffness, hydrophobic interactions of the side chains and the main-chain hydrogen bonds. Two types of approximations for the short-range interactions were compared: simple statistical potentials and knowledge-based protein-specific potentials derived from the sequence-structure compatibility of short fragments of protein chains. Model proteins in the denatured state are relatively compact, although the majority of the sampled conformations are globally different from the native fold. At the same time short protein fragments are mostly native-like. Thus, the denatured state of the model proteins has several features of the molten globule state observed experimentally. Statistical potentials induce native-like conformational propensities in the denatured state, especially for the fragments located in the core of folded proteins. Knowledge-based protein-specific potentials increase only slightly the level of similarity to the native conformations, in spite of their qualitatively higher specificity in the native structures. For a few cases, where fairly accurate experimental data exist, the simulation results are in semiquantitative agreement with the physical picture revealed by the experiments. This shows that the model studied in this work could be used efficiently in computational studies of protein dynamics in the denatured state, and consequently for studies of protein folding pathways, i.e. not only for the modeling of folded structures, as it was shown in previous studies. The results of the present studies also provide a new insight into the explanation of the Levinthal's paradox.
- Akiyama S, Takahashi S, Ishimori K, Morishima I (2000) Stepwise formation of alpha-helices during cytochrome c folding. Nat Struct Biol 7: 514-520.
- Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25: 3389-3402.
- Baker EN, Arcus VL, Lott JS (2003) Protein structure prediction and analysis as a tool for functional genomics. Appl Bioinformatics 2: S3-10.
- Bartlett GJ, Todd AE, Thornton JM (2003) Inferring protein function from structure. Methods Biochem Anal 44: 387-407.
- Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28: 235-242.
- Bolesta E, Kowalczyk A, Wierzbicki A, Rotkiewicz P, Bambach B, Tsao CY, Horwacik I, Kolinski A, Rokita H, Brecher M, Wang X, Ferrone S, Kozbor D (2005) DNA vaccine expressing the mimotope of GD2 ganglioside induces protective GD2 cross-reactive antibody responses. Cancer Res 65: 3410-3418.
- Bond CJ, Wong KB, Clarke J, Fersht AR, Daggett V (1997) Characterization of residual structure in the thermally denatured state of barnase by simulation and experiment: description of the folding pathway. Proc Natl Acad Sci USA 94: 13409-13413.
- Boniecki M, Rotkiewicz P, Skolnick J, Kolinski A (2003) Protein fragment reconstruction using various modeling techniques. J Comput Aided Mol Des 17: 725-738.
- Bonneau R, Strauss CE, Rohl CA, Chivian D, Bradley P, Malmstrom L, Robertson T, Baker D (2002) De novo prediction of three-dimensional structures for major protein families. J Mol Biol 322: 65-78.
- Brooks CL 3rd, Gruebele M, Onuchic JN, Wolynes PG (1998) Chemical physics of protein folding. Proc Natl Acad Sci USA 95: 11037-11038.
- Bujnicki JM, Rotkiewicz P, Kolinski A, Rychlewski L (2001) Three-dimensional modeling of the I-TevI homing endonuclease catalytic domain, a GIY-YIG superfamily member, using NMR restraints and Monte Carlo dynamics. Protein Eng 14: 717-721.
- Bushnell GW, Louie GV, Brayer GD (1990) High-resolution three-dimensional structure of horse heart cytochrome c. J Mol Biol 214: 585-595.
- Bycroft M, Matouschek A, Kellis JT Jr, Serrano L, Fersht AR (1990) Detection and characterization of a folding intermediate in barnase by NMR. Nature 346: 488-490.
- Bycroft M, Ludvigsen S, Fersht AR, Poulsen FM (1991) Determination of the three-dimensional solution structure of barnase using nuclear magnetic resonance spectroscopy. Biochemistry 30: 8697-8701.
- Chance MR, Fiser A, Sali A, Pieper U, Eswar N, Xu G, Fajardo JE, Radhakannan T, Marinkovic N (2004) High-throughput computational and experimental techniques in structural genomics. Genome Res 14: 2145-2154.
- Colon W, Elove GA, Wakem LP, Sherman F, Roder H (1996) Side chain packing of the N- and C-terminal helices plays a critical role in the kinetics of cytochrome c folding. Biochemistry 35: 5538-5549.
- Contreras-Moreira B, Fitzjohn PW, Bates PA (2002) Comparative modelling: an essential methodology for protein structure prediction in the post-genomic era. Appl Bioinformatics 1: 177-190.
- Dolgikh DA, Gilmanshin RI, Brazhnikov EV, Bychkova VE, Semisotnov GV, Venyaminov SY, Ptitsyn OB (1981) α-Lactalbumin: compact state with fluctuating tertiary structure? FEBS Lett 136: 311-313.
- Ekonomiuk D, Kielbasinski M, Kolinski A (2005) Protein modeling with a reduced representation: statistical potentials and protein folding mechanism. Acta Biochim Polon 52: 741-758.
- Feig M, Rotkiewicz P, Kolinski A, Skolnick J, Brooks CL 3rd (2000) Accurate reconstruction of all-atom protein representations from side-chain-based low-resolution models. Proteins 41: 86-97.
- Ferguson N, Fersht AR (2003) Early events in protein folding. Curr Opin Struct Biol 13: 75-81.
- Fersht AR (1993) The sixth Datta Lecture. Protein folding and stability: the pathway of folding of barnase. FEBS Lett 325: 5-16.
- Fersht AR (1997) Nucleation mechanisms in protein folding. Curr Opin Struct Biol 7: 3-9.
- Grantcharova VP, Baker D (1997) Folding dynamics of the src SH3 domain. Biochemistry 36: 15685-15692.
- Grantcharova VP, Riddle DS, Baker D (2000) Long-range order in the src SH3 folding transition state. Proc Natl Acad Sci USA 97: 7084-7089.
- Gront D, Kolinski A (2005) A new approach to prediction of short range conformational propensities in proteins. Bioinformatics 21: 981-987.
- Gront D, Kolinski A, Skolnick J (2000) Comparison of three Monte Carlo search strategies for a protein-like homopolymer model: folding thermodynamics and identification of low-energy structures. J Chem Phys 113: 5065-5071.
- Gront D, Kolinski A, Skolnick J (2001) A new combination of Replica Exchange Monte Carlo and histogram analysis for protein folding and thermodynamics. J Chem Phys 115: 1569-1574.
- Houry WA, Sauder JM, Roder H, Scheraga HA (1998) Definition of amide protection factors for early kinetic intermediates in protein folding. Proc Natl Acad Sci USA 95: 4299-4302.
- Karplus M, Weaver DL (1979) Diffusion-collision model for protein folding. Biopolymers 18: 1421-1437.
- Kazmirski SL, Wong KB, Freund SM, Tan YJ, Fersht AR, Daggett V (2001) Protein folding from a highly disordered denatured state: the folding pathway of chymotrypsin inhibitor 2 at atomic resolution. Proc Natl Acad Sci USA 98: 4349-4354.
- Klimov DK, Thirumalai D (2000) Mechanisms and kinetics of beta-hairpin formation. Proc Natl Acad Sci USA 97: 2544-2549.
- Kolinski A (2004) Protein modeling and structure prediction with a reduced representation. Acta Biochim Polon 51: 349-371.
- Kolinski A, Skolnick J (2004) Reduced models of proteins and their applications. Polymer 45: 511-524.
- Kolinski A, Betancourt M, Kihara D, Rotkiewicz P, Skolnick J (2001) Generalized comparative modeling (GENECOMP): a combination of sequence comparison, threading, lattice and off-lattice modeling for protein structure prediction and refinement. Proteins 44: 133-149.
- Kuwajima K (1989) The molten globule state as a clue for understanding the folding and cooperativity of globular protein structure. Proteins 6: 87-103.
- Levinthal C (1968) Are there pathways for protein folding? Chem Phys 65: 44-45.
- Li A, Daggett V (1998) Molecular dynamics simulation of the unfolding of barnase: characterization of the major intermediate. J Mol Biol 275: 677-694.
- Liwo A, Khalili M, Scheraga HA (2005) Ab initio simulations of protein-folding pathways by molecular dynamics with the united-residue model of polypeptide chains. Proc Natl Acad Sci USA 102: 2362-2367.
- Malolepsza E, Boniecki M, Kolinski A, Piela L (2005) Theoretical model of prion propagation: A misfolded protein induces misfolding. Proc Natl Acad Sci USA 102: 7835-7840.
- Marmorino JL, Pielak GJ (1995) A native tertiary interaction stabilizes the A state of cytochrome c. Biochemistry 34: 3140-3143.
- Navon A, Ittah V, Landsman P, Scheraga HA, Haas E (2001) Distributions of intramolecular distances in the reduced and denatured states of bovine pancreatic ribonuclease A. Folding initiation structures in the C-terminal portions of the reduced protein. Biochemistry 40: 105-118.
- Ohgushi M, Wada A (1983) Molten globule state: a compact form of globular proteins with mobile side-chains. FEBS Lett 164: 21-24.
- Oldziej S, Czaplewski C, Liwo A, Chinchio M, Nanias M, Vila JA, Khalili M, Arnautova YA, Jagielska A, Makowski M, Schafroth HD, Kazmierkiewicz R, Ripoll DR, Pillardy J, Saunders JA, Kang YK, Gibson KD, Scheraga HA (2005) Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: assessment in two blind tests. Proc Natl Acad Sci USA 102: 7547-7552.
- Plewczynska D, Kolinski A (2005) Protein folding with a reduced model and inacurate short-range restraints. Macromol Theory Simul 14: 444-451.
- Pokarowski P, Kloczkowski A, Jernigan RL, Kothari NS, Pokarowska M, Kolinski A (2005) Inferring ideal amino acid interaction forms from statistical protein contact potentials. Proteins 59: 49-57.
- Privalov PL, Tiktopulo EI, Venyaminov S, Griko Yu V, Makhatadze GI, Khechinashvili NN (1989) Heat capacity and conformation of proteins in the denatured state. J Mol Biol 205: 737-750.
- Ptitsyn OB (1995a) How the molten globule became. Trends Biochem Sci 20: 376-379.
- Ptitsyn OB (1995b) Molten globule and protein folding. Adv Protein Chem 47: 83-229.
- Ptitsyn OB, Pain RH, Semisotnov GV, Zerovnik E, Razgulyaev OI (1990) Evidence for a molten globule state as a general intermediate in protein folding. FEBS Lett 262: 20-24.
- Rotkiewicz P, Sicinska W, Kolinski A, DeLuca HF (2001) Model of three-dimensional structure of vitamin D receptor and its binding mechanism with 1alpha,25-dihydroxyvitamin D(3). Proteins 44: 188-199.
- Sali A (1998) 100,000 protein structures for the biologist. Nat Struct Biol 5: 1029-1032.
- Sauder JM, Roder H (1998) Amide protection in an early folding intermediate of cytochrome c. Fold Des 3: 293-301.
- Shastry MC, Roder H (1998) Evidence for barrier-limited protein folding kinetics on the microsecond time scale. Nat Struct Biol 5: 385-392.
- Sicinski RR, Rotkiewicz P, Kolinski A, Sicinska W, Prahl JM, Smith CM, DeLuca HF (2002) 2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain. J Med Chem 45: 3366-3380.
- Skolnick J, Fetrow JS, Kolinski A (2000) Structural genomics and its importance for gene function analysis. Nat Biotechnol 18: 283-287.
- Skolnick J, Kolinski A (1990) Simulations of the folding of a globular protein. Science 250: 1121-1125.
- Sosnick TR, Shtilerman MD, Mayne L, Englander SW (1997) Ultrafast signals in protein folding and the polypeptide contracted state. Proc Natl Acad Sci USA 94: 8545-8550.
- Swendsen RH, Wang JS (1986) Relica Monte Carlo simulations. Phys Rev Lett 57: 2607-2609.
- Whisstock JC, Lesk AM (2003) Prediction of protein function from protein sequence and structure. Q Rev Biophys 36: 307-340.
- Wong KB, Clarke J, Bond CJ, Neira JL, Freund SM, Fersht AR, Daggett V (2000) Towards a complete description of the structural and dynamic properties of the denatured state of barnase and the role of residual structure in folding. J Mol Biol 296: 1257-1282.
- Xie D, Freire E (1994) Molecular basis of cooperativity in protein folding. V. Thermodynamic and structural conditions for the stabilization of compact denatured states. Proteins 19: 291-301.
- Xu W, Harrison SC, Eck MJ (1997) Three-dimensional structure of the tyrosine kinase c-Src. Nature 385: 595-602.
- Zwanzig R, Szabo A, Bagchi B (1992) Levinthal's paradox. Proc Natl Acad Sci USA 89: 20-22.
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