Article
Exploring the free energy landscape of a model β-hairpin peptide and its isoform
Chitra Narayanan,
Cristiano L. Dias,
Corresponding Author
Chitra Narayanan
Department of Physics, New Jersey Institute of Technology, University Heights, Newark, New Jersey, 07102-1982
Correspondence to: Cristiano L. Dias, Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102. E-mail: [email protected] or Chitra Narayanan, Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Cristiano L. Dias
Department of Physics, New Jersey Institute of Technology, University Heights, Newark, New Jersey, 07102-1982
Correspondence to: Cristiano L. Dias, Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102. E-mail: [email protected] or Chitra Narayanan, Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102. E-mail: [email protected]Search for more papers by this authorChitra Narayanan,
Cristiano L. Dias,
Corresponding Author
Chitra Narayanan
Department of Physics, New Jersey Institute of Technology, University Heights, Newark, New Jersey, 07102-1982
Correspondence to: Cristiano L. Dias, Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102. E-mail: [email protected] or Chitra Narayanan, Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Cristiano L. Dias
Department of Physics, New Jersey Institute of Technology, University Heights, Newark, New Jersey, 07102-1982
Correspondence to: Cristiano L. Dias, Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102. E-mail: [email protected] or Chitra Narayanan, Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102. E-mail: [email protected]Search for more papers by this authorABSTRACT
Secondary structural transitions from α-helix to β-sheet conformations are observed in several misfolding diseases including Alzheimer's and Parkinson's. Determining factors contributing favorably to the formation of each of these secondary structures is therefore essential to better understand these disease states. β-hairpin peptides form basic components of anti-parallel β-sheets and are suitable model systems for characterizing the fundamental forces stabilizing β-sheets in fibrillar structures. In this study, we explore the free energy landscape of the model β-hairpin peptide GB1 and its E2 isoform that preferentially adopts α-helical conformations at ambient conditions. Umbrella sampling simulations using all-atom models and explicit solvent are performed over a large range of end-to-end distances. Our results show the strong preference of GB1 and the E2 isoform for β-hairpin and α-helical conformations, respectively, consistent with previous studies. We show that the unfolded states of GB1 are largely populated by misfolded β-hairpin structures which differ from each other in the position of the β-turn. We discuss the energetic factors contributing favorably to the formation of α-helix and β-hairpin conformations in these peptides and highlight the energetic role of hydrogen bonds and non-bonded interactions. Proteins 2014; 82:2394–2402. © 2014 Wiley Periodicals, Inc.
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REFERENCES
- 1Chiti F, Dobson CM. Protein misfolding, #functional |amyloid, and human disease. Annu Rev Biochem 2006; 75: 333–366.
- 2Selkoe DJ. Folding proteins in fatal ways. Nature 2003; 426: 900–904.
- 3Benzinger TL, Gregory DM, Burkoth TS, Miller-Auer H, Lynn DG, Botto RE, Meredith SC. Propagating structure of Alzheimer's β-amyloid (10-35) is parallel β-sheet with residues in exact register. Proc Natl Acad Sci USA 1998; 95: 13407–13412.
- 4Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, Schubert D, Riek R. 3D structure of Alzheimer's amyloid-β (1-42) fibrils. Proc Natl Acad Sci USA 2005; 102: 17342–17347.
- 5Antzutkin ON, Balbach JJ, Leapman RD, Rizzo NW, Reed J, Tycko R. Multiple quantum solid-state NMR indicates a parallel, #not |antiparallel, organization of β-sheets in Alzheimer's β-amyloid fibrils. Proc Natl Acad Sci USA 2000; 97: 13045–13050.
- 6Antzutkin ON, Leapman RD, Balbach JJ, Tycko R. Supramolecular structural constraints on Alzheimer's β-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry 2002; 41: 15436–15450.
- 7Chen M, Margittai M, Chen J, Langen R. Investigation of alpha-synuclein fibril structure by site-directed spin labeling. J Biol Chem 2007; 282: 24970–24979.
- 8Tycko R, Savtchenko R, Ostapchenko VG, Makarava N, Baskakov IV. The α-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel β-sheet structure in PrP fibrils: evidence from solid state nuclear magnetic resonance. Biochemistry 2010; 49: 9488–9497.
- 9Shewmaker F, Wickner RB, Tycko R. Amyloid of the prion domain of Sup35p has an in-register parallel β-sheet structure. Proc Natl Acad Sci USA 2006; 103: 19754–19759.
- 10Qiang W, Yau W-M, Luo Y, Mattson MP, Tycko R. Antiparallel β-sheet architecture in Iowa-mutant β-amyloid fibrils. Proc Natl Acad Sci USA 2012; 109: 4443–4448.
- 11Lansbury PT, Costa PR, Griffiths JM, Simon EJ, Auger M, Halverson KJ, Kocisko DA, Hendsch ZS, Ashburn TT, Spencer RG. Structural model for the β-amyloid fibril based on interstrand alignment of an antiparallel-sheet comprising a C-terminal peptide. Nat Struct Mol Biol 1995; 2: 990–998.
- 12Tycko R. Progress towards a molecular-level structural understanding of amyloid fibrils. Curr Opin Struct Biol 2004; 14: 96–103.
- 13Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJ, McFarlane HT. Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 2007; 447: 453–457.
- 14Makin OS, Atkins E, Sikorski P, Johansson J, Serpell LC. Molecular basis for amyloid fibril formation and stability. Proc Natl Acad Sci USA 2005; 102: 315–320.
- 15Marshall KE, Serpell LC. Insights into the structure of amyloid fibrils. Open Biol J 2009; 2: 185–192.
- 16Swietnicki W, Morillas M, Chen SG, Gambetti P, Surewicz WK. Aggregation and fibrillization of the recombinant human prion protein. huPrP90-231. Biochemistry 2000; 39: 424–431.
- 17Morillas M, Vanik DL, Surewicz WK. On the mechanism of α-helix to β-sheet transition in the recombinant prion protein. Biochemistry 2001; 40: 6982–6987.
- 18Pan K-M, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci USA 1993; 90: 10962–10966.
- 19Barrow CJ, Yasuda A, Kenny P, Zagorski MG. Solution conformations and aggregational properties of synthetic amyloid β peptides of Alzheimer's disease: analysis of circular dichroism spectra. J Mol Biol 1992; 225: 1075–1093.
- 20Olsen KA, Fesinmeyer RM, Stewart JM, Andersen NH. Hairpin folding rates reflect mutations within and remote from the turn region. Proc Natl Acad Sci USA 2005; 102: 15483–15487.
- 21Fesinmeyer RM, Hudson FM, Andersen NH. Enhanced hairpin stability through loop design: the case of the protein G B1 domain hairpin. J Am Chem Soc 2004; 126: 7238–7243.
- 22Booth DR, Sunde M, Bellotti V, Robinson CV, Hutchinson WL, Fraser PE, Hawkins PN, Dobson CM, Radford SE, Blake CC. Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 1997; 385: 787–793.
- 23Liu L, Cao Z. Turn-directed α-β conformational transition of α-syn12 peptide at different ph revealed by unbiased molecular dynamics simulations. Int J Mol Sci 2013; 14: 10896–10907.
- 24Kelly JW. The environmental dependency of protein folding best explains prion and amyloid diseases. Proc Natl Acad Sci USA 1998; 95: 930–932.
- 25Otzen DE, Kristensen O, Oliveberg M. Designed protein tetramer zipped together with a hydrophobic Alzheimer homology: a structural clue to amyloid assembly. Proc Natl Acad Sci USA 2000; 97: 9907–9912.
- 26López de la Paz M, de Mori G, Serrano L, Colombo G. Sequence dependence of amyloid fibril formation: insights from molecular dynamics simulations. J Mol Biol 2005; 349: 583–596.
- 27Gazit E. A possible role for π-stacking in the self-assembly of amyloid fibrils. FASEB J 2002; 16: 77–83.
- 28Levy Y, Jortner J, Becker OM. Solvent effects on the energy landscapes and folding kinetics of polyalanine. Proc Natl Acad Sci USA 2001; 98: 2188–2193.
- 29Dias CL, Karttunen M, Chan HS. Hydrophobic interactions in the formation of secondary structures in small peptides. Phys Rev E 2011; 84: 041931.
- 30Dias CL. Unifying microscopic mechanism for pressure and cold denaturations of proteins. Phys Rev Lett 2012; 109: 048104.
- 31Wei G, Shea JE. Effects of solvent on the structure of the Alzheimer amyloid-beta(25-35) peptide. Biophys J 2006; 91: 1638–1647.
- 32Daidone I, Simona F, Roccatano D, Broglia RA, Tiana G, Colombo G, Di Nola A. Beta-hairpin conformation of fibrillogenic peptides: structure and alpha-beta transition mechanism revealed by molecular dynamics simulations. Proteins 2004; 57: 198–204.
- 33Heller WT, Waring AJ, Lehrer RI, Huang HW. Multiple states of beta-sheet peptide protegrin in lipid bilayers. Biochemistry 1998; 37: 17331–17338.
- 34Chiti F, Calamai M, Taddei N, Stefani M, Ramponi G, Dobson CM. Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases. Proc Natl Acad Sci USA 2002; 99 Suppl 4: 16419–16426.
- 35Ding F, Borreguero JM, Buldyrey SV, Stanley HE, Dokholyan NV. Mechanism for the α-helix to β-hairpin transition. Proteins 2003; 53: 220–228.
- 36Singh S, Chiu C-C, Reddy AS, de Pablo JJ. α-helix to β-hairpin transition of human amylin monomer. J Chem Phys 2013; 138: 155101.
- 37Garcia AE, Sanbonmatsu KY. Exploring the energy landscape of a beta hairpin in explicit solvent. Proteins 2001; 42: 345–354.
10.1002/1097-0134(20010215)42:3<345::AID-PROT50>3.0.CO;2-H CAS PubMed Web of Science® Google Scholar
- 38Zagrovic B, Snow CD, Shirts MR, Pande VS. Simulation of folding of a small alpha-helical protein in atomistic detail using worldwide-distributed computing. J Mol Biol 2002; 323: 927–937.
- 39Ma B, Nussinov R. Molecular dynamics simulations of a beta-hairpin fragment of protein G: balance between side-chain and backbone forces. J Mol Biol 2000; 296: 1091–1104.
- 40Ma B, Nussinov R. Energy landscape and dynamics of the β-hairpin G peptide and its isomers: topology and sequences. Prot Sci 2003; 12: 1882–1893.
- 41Andrec M, Felts AK, Gallicchio E, Levy RM. Protein folding pathways from replica exchange simulations and a kinetic network model. Proc Natl Acad Sci USA 2005; 102: 6801–6806.
- 42Weinstock DS, Narayanan C, Felts AK, Andrec M, Levy RM, Wu KP, Baum J. Distinguishing among structural ensembles of the GB1 peptide: REMD simulations and NMR experiments. J Am Chem Soc 2007; 129: 4858–4859.
- 43Best RB, Mittal J. Balance between α and β structures in ab initio protein folding. J Phys Chem B 2010; 114: 8790–8798.
- 44Roccatano D, Amadei A, Nola AD, Berendsen HJ. A molecular dynamics study of the 41-56 β-hairpin from B1 domain of protein G. Prot Sci 1999; 8: 2130–2143.
- 45Pande VS, Rokhsar DS. Molecular dynamics simulations of unfolding and refolding of a beta-hairpin fragment of protein G. Proc Natl Acad Sci USA 1999; 96: 9062–9067.
- 46Zhou R, Berne BJ, Germain R. The free energy landscape for β-hairpin folding in explicit water. Proc Natl Acad Sci USA 2001; 98: 14931–14936.
- 47Wei G, Mousseau N, Derreumaux P. Complex folding pathways in a simple β-hairpin. Proteins 2004; 56: 464–474.
- 48Best RB, Mittal J. Microscopic events in β-hairpin folding from alternative unfolded ensembles. Proc Natl Acad Sci USA 2011; 108: 11087–11092.
- 49Gallicchio E, Andrec M, Felts AK, Levy RM. Temperature weighted histogram analysis method, #replica |exchange, and transition paths. J Phys Chem B 2005; 109: 6722–6731.
- 50Espinosa JF, Muñoz V, Gellman SH. Interplay between hydrophobic cluster and loop propensity in β-hairpin formation. J Mol Biol 2001; 306: 397–402.
- 51Klimov D, Thirumalai D. Mechanisms and kinetics of β-hairpin formation. Proc Natl Acad Sci USA 2000; 97: 2544–2549.
- 52Muñoz V, Henry ER, Hofrichter J, Eaton WA. A statistical mechanical model for β-hairpin kinetics. Proc Natl Acad Sci USA 1998; 95: 5872–5879.
- 53Juraszek J, Bolhuis PG. Effects of a mutation on the folding mechanism of a beta-hairpin. J Phys Chem B 2009; 113: 16184–16196.
- 54Torrie GM, Valleau JP. Nonphysical sampling distributions in Monte Carlo free-energy estimation: umbrella sampling. J Comput Phys 1977; 23: 187–199.
- 55Hess B, Kutzner C, van der Spoel D, Lindahl E. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 2008; 4: 435–447.
- 56Sorin EJ, Pande VS. Exploring the helix-coil transition via all-atom equilibrium ensemble simulations. Biophys J 2005; 88: 2472–2493.
- 57Best RB, Hummer G. Optimized molecular dynamics force fields applied to the helix-coil transition of polypeptides. J Phys Chem B 2009; 113: 9004–9015.
- 58Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 2010; 78: 1950–1958.
- 59Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys 1983; 79: 926–935.
- 60Bussi G, Donadio D, Parrinello M. Canonical sampling through velocity rescaling. J Chem Phys 2007; 126: 014101–014101.
- 61Parrinello M, Rahman A. Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 1981; 52: 7182.
- 62Kumar S, Rosenberg JM, Bouzida D, Swendsen RH, Kollman PA. The weighted histogram analysis method for free energy calculations on biomolecules. I. The method. J Comput Chem 1992; 13: 1011–1021.
- 63Hub JS, de Groot BL, van der Spoel D. g_wham—a free weighted histogram analysis implementation including robust error and autocorrelation estimates. J Chem Theory Comput 2010; 6: 3713–3720.
- 64Kabsch W, Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 1983; 22: 2577–2637.
- 65Daura X, Gademann K, Jaun B, Seebach D, van Gunsteren WF, Mark AE. Peptide folding: when simulation meets experiment. Angew Chem Int Ed 1999; 38: 236–240.
10.1002/(SICI)1521-3773(19990115)38:1/2<236::AID-ANIE236>3.0.CO;2-M CAS Web of Science® Google Scholar
- 66Chetty PS, Mayne L, Lund-Katz S, Stranz D, Englander SW, Phillips MC. Helical structure and stability in human apolipoprotein AI by hydrogen exchange and mass spectrometry. Proc Natl Acad Sci USA 2009; 106: 19005–19010.
- 67Daggett V, Levitt M. Molecular dynamics simulations of helix denaturation. J Mol Biol 1992; 223: 1121–1138.
- 68Hansmann UHE, Okamoto Y. Finite-size scaling of helix-coil transitions in poly-alamine studied by multicanonical simulations. J Chem Phys 1999; 110: 1267–1276.
- 69Bonomi M, Branduardi D, Gervasio FL, Parrinello M. The unfolded ensemble and folding mechanism of the C-terminal GB1 β-hairpin. J Am Chem Soc 2008; 130: 13938–13944.
- 70Yoda T, Sugita Y, Okamoto Y. Cooperative folding mechanism of a β-hairpin peptide studied by a multicanonical replica-exchange molecular dynamics simulation. Proteins 2007; 66: 846–859.
- 71Zhou R, Berne BJ, Germain R. The free energy landscape for beta hairpin folding in explicit water. Proc Natl Acad Sci USA 2001; 98: 14931–14936.
- 72Enemark S, Kurniawan NA, Rajagopalan R. β-hairpin forms by rolling up from C-terminal: topological guidance of early folding dynamics. Sci Rep 2012; 2: 649.
- 73Schellman JA. The stability of hydrogen-bonded peptide structures in aqueous solution. Comptes rendus des travaux du Laboratoire Carlsberg. Série chimique 1955; 29.
- 74Kauzmann W. Some factors in the interpretation of protein denaturation. Adv Protein Chem 1959; 14: 1–63.
- 75Baldwin RL. In search of the energetic role of peptide hydrogen bonds. J Biol Chem 2003; 278: 17581–17588.
- 76Jorgensen WL. Interactions between amides in solution and the thermodynamics of weak binding. J Am Chem Soc 1989; 111: 3770–3771.
- 77Narayanan C, Dias CL. Hydrophobic interactions and hydrogen bonds in β-sheet formation. J Chem Phys 2013; 139.
- 78Evans DA, Wales DJ. Folding of the GB1 hairpin peptide from discrete path sampling. J Chem Phys 2004; 121: 1080–1090.
- 79Morillas M, Vanik DL, Surewicz WK. On the mechanism of α-helix to β-sheet transition in the recombinant prion protein. Biochemistry 2001; 40: 6982–6987.
- 80Xu Y, Shen J, Luo X, Zhu W, Chen K, Ma J, Jiang H. Conformational transition of amyloid β-peptide. Proc Natl Acad Sci USA 2005; 102: 5403–5407.
- 81Zhou X, Alber F, Folkers G, Gonnet GH, Chelvanayagam G. An analysis of the helix-to-strand transition between peptides with identical sequence. Proteins 2000; 41: 248–256.
10.1002/1097-0134(20001101)41:2<248::AID-PROT90>3.0.CO;2-J CAS PubMed Web of Science® Google Scholar
- 82Mou CY, Lin CY, Chen NY. Folding a protein with equal probability of being helix or hairpin. Biophys J 2012; 103: 99–108.
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