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2006 | 53 | 1 | 121-130
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Free energy of helix propagation in short polyalanine chains determined from peptide growth simulations of La3+-binding model peptides. Comparison with experimental data

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Molecular dynamics (MD) is, at present, a unique tool making it possible to study, at the atomic level, conformational transitions in peptides and proteins. Nevertheless, because MD calculations are always based on a more or less approximate physical model, using a set of approximate parameters, their reliability must be tested by comparison with experimental data. Unfortunately, it is very difficult to find a peptide system in which conformational transitions can be studied both experimentally and using MD simulations so that a direct comparison of the results obtained in both ways could be made. Such a system, containing a rigid α-helix nucleus stabilized by La3+ coordination to a 12-residue sequence taken from an EF-hand protein has recently been used to determine experimentally the helix propagation parameters in very short polyalanine segments (Goch et al. (2003) Biochemistry 42: 6840-6847). The same parameters were calculated here for the same peptide system using the peptide growth simulation method with, alternatively, charmm 22 and cedar potential energy functions. The calculated free energies of the helix-coil transition are about two times too large for cedar and even three times too large for charmm 22, as compared with the experimental values. We suggest that these discrepancies have their origin in the incorrect representation of unfolded peptide backbone in solution by the molecular mechanics force fields.

Physical description
  • Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland
  • Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, USA
  • Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland
  • Allen MP, Tildesley DJ (1987) Computer Simulation of Liquids. Oxford University Press, New York.
  • Armen R, Alonso DO, Daggett V (2003) The role of α-, 310-, and π-helix in helix-->coil transitions. Protein Sci 12: 1145-1157.
  • Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81: 3684-3690.
  • Brunger AT (1992) X-PLOR, a System for X-ray Crystallography and NMR. Yale University Press, New Haven, CT.
  • Daggett V, Levitt M (1992) Molecular dynamics simulations of helix denaturation. J Mol Biol 223: 1121-1138.
  • Daggett V, Kollman PA, Kuntz ID (1991) A molecular dynamics simulation of polyalanine: an analysis of equilibrium motions and helix-coil transitions. Biopolymers 31: 1115-1134.
  • Darden TA, York DM, Pedersen LG (1993) Particle mesh Ewald: an N.log(N) method for Ewald sums in large systems. J Chem Phys 98: 10089-10092.
  • Daura X, van Gunsteren WF, Rigo D, Juan B, Seebach D (1997) Studying the stability of a helical β-heptapeptide by molecular dynamics simulation. Chem Eur J 3: 1410-1417.
  • Daura X, Jaun B, Seebach D, van Gunsteren WF, Mark AE (1998) Reversible peptide folding in solution by molecular dynamics simulation. J Mol Biol 280: 925-932.
  • Daura X, van Gunsteren WF, Mark AE (1999) Folding-unfolding thermodynamics of a β-heptapeptide from equilibrium simulations. Proteins 34: 269-280.
  • DiCapua FM, Swaminathan S, Berveridge DL (1990) Theoretical evidence for destabilization of an α-helix by water insertion: Molecular dynamics of hydrated decaalanine. J Am Chem Soc 112: 6768-6771.
  • Doig AJ (2002) Recent advances in helix-coil theory. Biophys Chem 101/102: 281-293.
  • Elstner M, Porezag D, Jungnickel G, Elsner J, Haugk M, Frauenheim T, Suhai S, Seifert G (1998) Self-consistent-charge density-functional tight-binding method for simulations of complex materials properties. Phys Rev B 58: 7260-7268.
  • Ferro DR, McQueen JE Jr, McCown JT, Hermans J (1980) Energy minimizations of rubredoxin. J Mol Biol 136: 1-18.
  • Garcia AE, Sanbonmatsu KY (2002) α-Helical stabilization by side chain shielding of backbone hydrogen bonds. Proc Natl Acad Sci USA 99: 2782-2787.
  • Goch G, Maciejczyk M, Oleszczuk M, Stachowiak D, Malicka J, Bierzynski A (2003) Experimental investigation of initial steps of helix propagation in model peptides. Biochemistry 42: 6840-6847.
  • Hermans J, Berendsen HJC, van Gunsteren WF, Postma JPM (1984) A consistent empirical potential for water-protein interactions. Biopolymers 23: 1513-1518.
  • Hermans J, Yun RH, Anderson AG (1992) Precision of free energies calculated by molecular dynamics simulations of peptides in solution. J Comp Chem 13: 429-442.
  • Hill TL (1986) An Introduction to Statistical Thermodynamics. Dover Publications Inc., New York.
  • Hu H, Yun RH, Hermans J (2002) Reversibility of free energy simulations: Slow growth may have a unique advantage. Mol Simul 28: 67-80.
  • Hu H, Elstner M, Hermans J (2003) Comparison of a QM/MM force field and molecular mechanics force fields in simulations of alanine and glycine "dipeptides" (Ace-Ala-Nme and Ace-Gly-Nme) in water in relation to the problem of modeling the unfolded peptide backbone in solution. Proteins 50: 451-463.
  • Hummer G, Garcia AE, Garde S (2000) Conformational diffusion and helix formation kinetics. Phys Rev Lett 85: 2637-2640.
  • Hummer G, Garcia AE, Garde S (2001) Helix nucleation kinetics from molecular simulations in explicit solvent. Proteins 42: 77-84.
  • Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79: 926-935.
  • Lee KH, Benson DR, Kuczera K (2000) Transitions from α to π helix observed in molecular dynamics simulations of synthetic peptides. Biochemistry 39: 13737-13747.
  • MacKerell AD Jr, Bashford D, Bellott M, Dunbrack RL Jr, Evanseck JD, Field MJ, Fisher S, Gao J, Guo H, Ha S, Nguyen DT, Prodhom B, Reiher III WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiórkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102: 3586-3616.
  • MacKerell AD Jr, Feig M, Brooks CL 3rd (2004) Improved Treatment of the protein backbone in empirical force fields. J Am Chem Soc 126: 698-699.
  • Mann G, Yun RH, Nyland L, Prins J, Board J, Hermans J (2002) Sigma MD Program and a generic interface applicable to multifunctional programs with complex, hierarchical command structure. In Computational Methods for Macromolecules: Challanges and Applications (Schlick T, Gan HH, eds). Proc 3rd Int Workshop: Algorithms for Macromolecular Modeling. October 12-14, 2000, Springer-Verlag, Berlin, New York.
  • Poland D, Scheraga HA (1970) Theory of Helix-coil Transitions in Biopolymers. Academic Press, New York and London.
  • Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alcanes. J Comp Phys 23: 327-341.
  • Schellman JA (1955) The stability of hydrogen-bonded peptide structures in aqueous solution. C R Trav Lab Carlsberg (Chim) 29: 230-259.
  • Schlick T, Skeel RD, Brunger AT, Kale LV, Board JA, Hermans J, Schulten K (1999) Algorythmic challenges in computational molecular biophysics. J Comp Phys 151: 9-48.
  • Siedlecka M, Goch G, Ejchart A, Sticht H, Bierzyski A (1999) α-Helix nucleation by a calcium-binding peptide loop. Proc Natl Acad Sci USA 96: 903-908.
  • Smith PE (1999) The alanine dipeptide free energy surface in solution. J Chem Phys 111: 5568-5579.
  • Soman KV, Karimi A, Case DA (1991) Unfolding of an α-helix in water. Biopolymers 31: 1351-1361.
  • Straatsma TP, Berendsen HJC, Stam A (1986) Estimation of statistical errors in molecular simulation calculations. Mol Phys 57: 89-95.
  • Sugita Y, Okamoto Y (1999) Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett 314: 141-151.
  • Tirado-Rives J, Jorgensen WL (1991) Molecular dynamics simulations of the unfolding of an α-helical analogue of ribonuclease A S-peptide in water. Biochemistry 30: 3864-3871.
  • Tobias DJ, Brooks CL 3rd (1991) Thermodynamics and mechanism of α helix initiation in alanine and valine peptides. Biochemistry 30: 6059-6070.
  • Tuckerman ME, Berne BJ, Martyna GJ (1992) Reversible multiple time scale molecular dynamics. J Chem Phys 97: 1990-2001.
  • Wang L, O'Connell T, Tropsha A, Hermans J (1995) Thermodynamic parameters for the helix-coil transition of oligopeptides: molecular dynamics simulation with the peptide growth method. Proc Natl Acad Sci USA 92: 10924-1098.
  • Young WS, Brooks CL 3rd (1996) A microscopic view of helix propagation: N and C-terminal helix growth in alanine helices. J Mol Biol 259: 560-572.
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