Hostname: page-component-8448b6f56d-c47g7 Total loading time: 0 Render date: 2024-04-20T04:17:25.678Z Has data issue: false hasContentIssue false
  • English
  • Français

Using DelPhi Capabilities to Mimic Protein’s Conformational Reorganization with Amino Acid Specific Dielectric Constants

Published online by Cambridge University Press:  03 June 2015

Lin Wang ,
Zhe Zhang ,
Walter Rocchia  and
Emil Alexov
Lin Wang*
Affiliation:
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
Zhe Zhang*
Affiliation:
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
Walter Rocchia*
Affiliation:
Drug Discovery and Development, Italian Institute of Technology, via Morego 30, 16163 Genova, Italy
Emil Alexov*
Affiliation:
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
*
Email:lwang3@clemson.edu
Email:zz@clemson.edu
Email:Walter.Rocchia@iit.it
Corresponding author.Email:ealexov@clemson.edu
Get access

Abstract

Many molecular events are associated with small or large conformational changes occurring in the corresponding proteins. Modeling such changes is a challenge and requires significant amount of computing time. From point of view of electrostatics, these changes can be viewed as a reorganization of local charges and dipoles in response to the changes of the electrostatic field, if the cause is insertion or deletion of a charged amino acid. Here we report a large scale investigation of modeling the changes of the folding energy due to single mutations involving charged group. This allows the changes of the folding energy to be considered mostly electrostatics in origin and to be calculated with DelPhi assigning residue-specific value of the internal dielectric constant of protein. The predicted energy changes are benchmarked against experimentally measured changes of the folding energy on a set of 257 single mutations. The best fit between experimental values and predicted changes is used to find out the effective value of the internal dielectric constant for each type of amino acid. The predicted folding free energy changes with the optimal, amino acid specific, dielectric constants are within RMSD=0.86 kcal/mol from experimentally measured changes.

Keywords

82.20.WtDelPhiprotein electrostaticsdielectric constantPoisson-Boltzmann equationprotein flexibilityenergy calculationssingle point mutations
Type
Research Article
Information
Communications in Computational Physics , Volume 13 , Issue 1 , January 2013 , pp. 13 - 30
Copyright
Copyright © Global Science Press Limited 2013

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

[1]Perutz, MF: Electrostatic effects in proteins. Science 1978, 201(4362): 1187–1191.Google Scholar
[2]Warshel, A, Russell, ST: Calculations of electrostatic interactions in biological systems and in solutions. Q Rev Biophys 1984, 17(3): 283–422.Google Scholar
[3]Sharp, KA, Honig, B: Electrostatic interactions in macromolecules: theory and applications. Annu Rev Biophys Biophys Chem 1990, 19: 301–332.Google Scholar
[4]Simonson, T: Dielectric relaxation in proteins: microscopic and macroscopic models. Int J Quantum Chem 1999, 73(1): 45–57.3.0.CO;2-Q>CrossRefGoogle Scholar
[5]Van Belle, D, Couplet, I, Prevost, M, Wodak, SJ: Calculations of electrostatic properties in proteins: Analysis of contributions from induced protein dipoles. J Mol Biol 1987, 198(4): 721–735.CrossRefGoogle ScholarPubMed
[6]Spassov, V, Bashford, D: Electrostatic coupling to pH-titrating sites as a source of cooperativity in protein-ligand binding. Protein Sci 1998,7(9): 2012–2025.CrossRefGoogle ScholarPubMed
[7]Misra, VK, Hecht, JL, Yang, AS, Honig, B: Electrostatic Contributions to the Binding Free Energy of the λ cI Repressor to DNA. Biophys J 1998, 75(5): 2262–2273.CrossRefGoogle Scholar
[8]Alexov, E: Numerical calculations of the pH of maximal protein stability. The effect of the sequence composition and three-dimensional structure. Eur J Biochem 2004, 271(1): 173–185.CrossRefGoogle Scholar
[9]Alexov, E, Honig, B: The origins of pH dependent effects on protein stability: Applications to proteases. Biophys J 2002,82(1): 474a–474a.Google Scholar
[10]Yang, AS, Honig, B: On the pH dependence of protein stability. J Mol Biol 1993,231(2): 459–474.Google Scholar
[11]Talley, K, Kundrotas, P, Alexov, E: Modeling salt dependence of protein-protein association: Linear vs non-linear Poisson-Boltzmann equation. Commun Comput Phys 2008, 3(5): 1071–1086.Google Scholar
[12]Bertonati, C, Honig, B, Alexov, E: Poisson-Boltzmann calculations of nonspecific salt effects on protein-protein binding free energies. Biophys J 2007, 92(6): 1891–1899.CrossRefGoogle ScholarPubMed
[13]King, G, Warshel, A: A surface constrained all atom solvent model for effective simulations of polar solutions. J Chem Phys 1989, 91: 3647.Google Scholar
[14]Still, WC, Tempczyk, A, Hawley, RC, Hendrickson, T: Semianalytical treatment of solvation for molecular mechanics and dynamics. J Am Chem Soc 1990, 112(16): 6127–6129.CrossRefGoogle Scholar
[15]Kony, DB, Damm, W, Stoll, S, van Gunsteren, WF, Hunenberger, PH: Explicit-solvent molecular dynamics simulations of the polysaccharide schizophyllan in water. Biophys J 2007, 93(2): 442–455.Google Scholar
[16]Druchok, M, Vlachy, V, Dill, KA: Explicit-water molecular dynamics study of a short-chain 3,3 ionene in solutions with sodium halides. J Chem Phys 2009,130(13): 134903.Google Scholar
[17]Grochowski, P, Trylska, J: Continuum molecular electrostatics, salt effects, and counterion binding – a review of the Poisson-Boltzmann theory and its modifications. Biopolymers 2008,89(2): 93–113.CrossRefGoogle Scholar
[18]Olkhova, E, Hunte, C, Screpanti, E, Padan, E, Michel, H: Multiconformation continuum electrostatics analysis of the NhaA Na+/H+ antiporter of Escherichia coli with functional implications. Proc Natl Acad Sci U S A 2006,103(8): 2629–2634.CrossRefGoogle ScholarPubMed
[19]Hassan, SA, Mehler, EL: A critical analysis of continuum electrostatics: the screened Coulomb potential – implicit solvent model and the study of the alanine dipeptide and discrimination of misfolded structures of proteins. Proteins 2002,47(1): 45–61.Google Scholar
[20]Olson, MA: Modeling loop reorganization free energies of acetylcholinesterase: a comparison of explicit and implicit solvent models. Proteins: Structure, Function, and Bioinformatics 2004,57(4): 645–650.Google Scholar
[21]Gorham, RD Jr., Kieslich, CA, Nichols, A, Sausman, NU, Foronda, M, Morikis, D: An evaluation of poisson-boltzmann electrostatic free energy calculations through comparison with experimental mutagenesis data. Biopolymers 2011.Google Scholar
[22]Bertonati, C, Honig, B, Alexov, E: Poisson-Boltzmann calculations of nonspecific salt effects on protein-protein binding free energies. Biophys J 2007, 92(6): 1891–1899.CrossRefGoogle ScholarPubMed
[23]Lee, MS, Salsbury, FR Jr, Olson, MA: An efficient hybrid explicit/implicit solvent method for biomolecular simulations. J Comput Chem 2004, 25(16): 1967–1978.CrossRefGoogle ScholarPubMed
[24]Ma, B, Nussinov, R: Explicit and implicit water simulations of a beta-hairpin peptide. Proteins 1999,37(1): 73–87.Google Scholar
[25]Spaeth, JR, Kevrekidis, IG, Panagiotopoulos, AZ: A comparison of implicit- and explicit-solvent simulations of self-assembly in block copolymer and solute systems. J Chem Phys 2011,134(16): 164902.Google Scholar
[26]Brancato, G, Rega, N, Barone, V: A hybrid explicit/implicit solvation method for first-principle molecular dynamics simulations. J Chem Phys 2008, 128(14): 144501.Google Scholar
[27]Song, X: An inhomogeneous model of protein dielectric properties: Intrinsic polarizabilities of amino acids. J Chem Phys 2002, 116: 9359.CrossRefGoogle Scholar
[28]Voges, D, Karshikoff, A: A model of a local dielectric constant in proteins. J Chem Phys 1998, 108: 2219.CrossRefGoogle Scholar
[29]Richards, FM: Areas, volumes, packing, and protein structure. Ann Rev Biophys Bioeng 1977, 6(1): 151–176.Google Scholar
[30]Alexov, E, Gunner, M: Calculated protein and proton motions coupled to electron transfer: electron transfer from QA-to QB in bacterial photosynthetic reaction centers. Biochemistry 1999,38(26): 8253–8270.Google Scholar
[31]Porschke, D: Electrostatics and electrodynamics of bacteriorhodopsin. Biophys J 1996, 71(6): 3381–3391.Google Scholar
[32]Böttcher, CJF, Van Belle, O, Bordewijk, P, Rip, A: Theory of Electric Polarization: Elsevier Scientific Pub. Co.; 1978.Google Scholar
[33]Gilson, MK, Honig, BH: The dielectric constant of a folded protein. Biopolymers 1986, 25(11): 2097–2119.Google Scholar
[34]King, G, Lee, FS, Warshel, A: Microscopic simulations of macroscopic dielectric constants of solvated proteins. J Chem Phys 1991,95: 4366.Google Scholar
[35]Antosiewicz, J, McCammon, JA, Gilson, MK: Prediction of pH-dependent properties of proteins. J Mol Biol 1994, 238(3): 415–436.Google Scholar
[36]Nakamura, H, Sakamoto, T, Wada, A: A theoretical study of the dielectric constant of protein. Protein Engineering 1988, 2(3): 177.Google Scholar
[37]Smith, PE, Brunne, RM, Mark, AE, Van Gunsteren, WF: Dielectric properties of trypsin inhibitor and lysozyme calculated from molecular dynamics simulations. J Phys Chem 1993, 97(9): 2009–2014.Google Scholar
[38]Honig, B, Nicholls, A: Classical electrostatics in biology and chemistry. Science 1995, 268(5214): 1144.CrossRefGoogle ScholarPubMed
[39]Schaefer, M, Sommer, M, Karplus, M: pH-dependence of protein stability: Absolute electrostatic free energy differences between conformations. J Phys Chem B 1997,101(9): 1663–1683.Google Scholar
[40]Dong, F, Zhou, HX: Electrostatic contributions to T4 lysozyme stability: Solvent-exposed charges versus semi-buried salt bridges. Biophys J 2002,83(3): 1341–1347.CrossRefGoogle ScholarPubMed
[41]Dong, F, Vijayakumar, M, Zhou, HX: Comparison of calculation and experiment implicates significant electrostatic contributions to the binding stability of barnase and barstar. Biophys J 2003, 85(1): 49–60.CrossRefGoogle Scholar
[42]Qin, S, Zhou, HX: Do electrostatic interactions destabilize protein-nucleic acid binding? Biopolymers 2007,86(2): 112–118.CrossRefGoogle ScholarPubMed
[43]Alexov, E: Role of the protein side-chain fluctuations on the strength of pair-wise electrostatic interactions: comparing experimental with computed pK(a)s. Proteins 2003, 50(1): 94–103.Google Scholar
[44]Talley, K, Ng, C, Shoppell, M, Kundrotas, P, Alexov, E: On the electrostatic component of protein-protein binding free energy. PMC Biophys 2008, 1(1): 2.CrossRefGoogle ScholarPubMed
[45]Baran, KL, Chimenti, MS, Schlessman, JL, Fitch, Ca, Herbst, KJ, Garcia-Moreno, BE: Electrostatic effects in a network of polar and ionizable groups in staphylococcal nuclease. J Mol Biol 2008,379(5): 1045–1062.Google Scholar
[46]Lee, KK, Fitch, CA, García-Moreno, EB: Distance dependence and salt sensitivity of pairwise, coulombic interactions in a protein. Protein science 2002, 11(5): 1004–1016.Google Scholar
[47]Bava, KA, Gromiha, MM, Uedaira, H, Kitajima, K, Sarai, A: ProTherm, version 4.0: thermodynamic database for proteins and mutants. Nucleic acids research 2004,32(suppl 1): D120.CrossRefGoogle ScholarPubMed
[48]Berman, HM, Westbrook, J, Feng, Z, Gilliland, G, Bhat, T, Weissig, H, Shindyalov, IN, Bourne, PE: The protein data bank. Nucleic acids research 2000, 28(1): 235.Google Scholar
[49]Sanner, MF, Olson, AJ, Spehner, JC: Reduced surface: an efficient way to compute molecular surfaces. Biopolymers 1996,38(3): 305–320.3.0.CO;2-Y>CrossRefGoogle ScholarPubMed
[50]Ponder, JW: TINKER: software tools for molecular design. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO 1998.Google Scholar
[51]Wang, J, Wolf, RM, Caldwell, JW, Kollman, PA, Case, DA: Development and testing of a general amber force field. J Comput Chem 2004, 25(9): 1157–1174.Google Scholar
[52]Witham, S, Takano, K, Schwartz, C, Alexov, E: A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics. Proteins 2011.Google Scholar
[53]Zhang, Z, Norris, J, Schwartz, C, Alexov, E: In silico and in vitro investigations of the mutability of disease-causing missense mutation sites in spermine synthase. PLoS One 2011, 6(5): e20373.Google Scholar
[54]Zhang, Z, Teng, S, Wang, L, Schwartz, CE, Alexov, E: Computational analysis of missense mutations causing Snyder-Robinson syndrome. Hum Mutat 2010, 31(9): 1043–1049.Google Scholar
[55]Rocchia, W, Alexov, E, Honig, B: Extending the applicability of the nonlinear Poisson-Boltzmann equation: Multiple dielectric constants and multivalent ions. J Phys Chem B 2001, 105(28): 6507–6514.Google Scholar
[56]Rocchia, W, Sridharan, S, Nicholls, A, Alexov, E, Chiabrera, A, Honig, B: Rapid grid based construction of the molecular surface and the use of induced surface charge to calculate reaction field energies: Applications to the molecular systems and geometric objects. J Comput Chem 2002, 23(1): 128–137.Google Scholar
[57]Brooks, BR, Bruccoleri, RE, Olafson, BD: CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 1983, 4(2): 187–217.Google Scholar
[58]Jorgensen, WL, Tirado-Rives, J: The OPLS (optimized potentials for liquid simulations) potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. J Am Chem Soc 1988,110(6): 1657–1666.Google Scholar
[59]Madura, JD, Briggs, JM, Wade, RC, Davis, ME, Luty, BA, Ilin, A, Antosiewicz, J, Gilson, MK, Bagheri, B, Scott, LR: Electrostatics and diffusion of molecules in solution: simulations with the University of Houston Brownian Dynamics program. Comp Phys Commun 1995, 91(1-3): 57–95.Google Scholar