Journal of Biological Physics

, Volume 31, Issue 3–4, pp 433–452 | Cite as

Protein Surface Dynamics: Interaction with Water and Small Solutes

  • Ran Friedman
  • Esther Nachliel
  • Menachem Gutman


Previous time resolved measurements had indicated that protons could propagate on the surface of a protein, or a membrane, by a special mechanism that enhances the shuttle of the proton towards a specific site [1]. It was proposed that a proper location of residues on the surface contributes to the proton shuttling function. In the present study, this notion was further investigated using molecular dynamics, with only the mobile charge replaced by Na+ and Cl ions. A molecular dynamics simulation of a small globular protein (the S6 of the bacterial ribosome) was carried out in the presence of explicit water molecules and four pairs of Na+ and Cl ions. A 10 ns simulation indicated that the ions and the protein's surface were in equilibrium, with rapid passage of the ions between the protein's surface and the bulk. Yet it was noted that, close to some domains, the ions extended their duration near the surface, suggesting that the local electrostatic potential prevented them from diffusing to the bulk. During the time frame in which the ions were detained next to the surface, they could rapidly shuttle between various attractor sites located under the electrostatic umbrella. Statistical analysis of molecular dynamics and electrostatic potential/entropy consideration indicated that the detainment state is an energetic compromise between attractive forces and entropy of dilution. The similarity between the motion of free ions next to a protein and the proton transfer on the protein's surface are discussed.

Key words

molecular dynamics ions at interface protein-salt interactions 


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  1. Nachliel, E., Gutman, M., Tittor, J. and Oesterhelt, D.: Proton Transfer Dynamics on the Surface of the Late M State of Bacteriorhodopsin, Biophys. J. 83 (2002), 416–426.ADSGoogle Scholar
  2. Bizzarri, A.R. and Cannistraro, S.: Molecular Dynamics of Water at the Protein-Solvent Interface, J. Phys. Chem. B 106 (2002), 6617–6633.CrossRefGoogle Scholar
  3. Makarov, V., Pettitt, B.M. and Feig, M.: Solvation and Hydration of Proteins and Nucleic Acids: A Theoretical View of Simulation and Experiment, Acc. Chem. Res. 35 (2002), 376–384.CrossRefGoogle Scholar
  4. Svergun, D.I., Richard, S., Koch, M.H., Sayers, Z., Kuprin, S. and Zaccai, G.: Protein Hydration in Solution: Experimental Observation by X-ray and Neutron Scattering, Proc. Natl. Acad. Sci. U.S. A. 95 (1998), 2267–2272.CrossRefADSGoogle Scholar
  5. Smith, J.C., Merzel, F., Verma, C.S. and Fischer, S.: Protein Hydration Water: Structure and Thermodynamics, J. Mol. Liquid 101 (2002), 27–33.Google Scholar
  6. Schiffer, C.A. and van Gunsteren, W.F.: Accessibility and Order of Water Sites in and Around Proteins: A Crystallographic Time-Averaging Study, Proteins 36 (1999), 501–511.CrossRefGoogle Scholar
  7. Sanschagrin, P.C. and Kuhn, L.A.: Cluster Analysis of Consensus Water Sites in Thrombin and Trypsin Shows Conservation Between Serine Proteases and Contributions to Ligand Specificity, Protein Sci. 7 (1998), 2054–2064.CrossRefGoogle Scholar
  8. Fenimore, P.W., Frauenfelder, H., McMahon, B.H. and Parak, F.G.: Slaving: Solvent Fluctuations Dominate Protein Dynamics and Functions, Proc. Natl. Acad. Sci. U.S.A. 99 (2002), 16047–16051.CrossRefADSGoogle Scholar
  9. Higo, J. and Nakasako, M.: Hydration Structure of Human Lysozyme Investigated by Molecular Dynamics Simulation and Cryogenic X-Ray Crystal Structure Analyses: On the Correlation Between Crystal Water Sites, Solvent Density, and Solvent Dipole, J. Comput. Chem. 23 (2002), 1323–1336.CrossRefGoogle Scholar
  10. Curtis, R.A., Prausnitz, J.M. and Blanch, H.W.: Protein-Protein and Protein-Salt Interactions in Aqueous Protein Solutions Containing Concentrated Electrolytes, Biotechnol. Bioeng. 57 (1998), 11–21.CrossRefGoogle Scholar
  11. Scheiner, S.: Quantum Chemical Studies of Proton Transport Through Biomembranes, Ann. N.Y. Acad. Sci. 367 (1981), 493–509.ADSGoogle Scholar
  12. Gutman, M., Huppert, D. and Nachliel, E.: Kinetic Studies of Proton Transfer in the Microenvironment of a Binding Site, Eur. J. Biochem. 121 (1982), 637–642.CrossRefGoogle Scholar
  13. Paddock, M.L., McPherson, P.H., Feher, G. and Okamura, M.Y.: Pathway of Proton Tranfer in Bacterial Reaction Centers: Replacement of Serinve-L22 by Alanine Inhibits Electron and Proton Transfers Associated with Reduction of Quinone to Dihydroquinone, Proc. Natl. Acad. Sci. U.S.A. 87 (1990), 6803–6807.ADSGoogle Scholar
  14. Bashford, D. and Gerwert, K.: Electrostatic Calculations of the pKa Values of Ionizable Groups in Bacteriorhodopsin, J. Mol. Biol. 224 (1992), 473–486.CrossRefGoogle Scholar
  15. Heberle, J., Riesle, J., Thiedemann, G., Oesterhelt, D. and Dencher, N.A.: Proton Migration Along the Membrane Surface and Retarded Surface to Bulk Transfer, Nature 370 (1994), 379–382.CrossRefADSGoogle Scholar
  16. McPherson, P.H., Schonfeld, M., Paddock, M.L., Okamura, M.Y. and Feher, G.: Protonation and Free Energy Changes Associated with Formation of QBH2 in Native and Glu-L212→Gln Mutant Reaction Centers from Rhodobacter Sphaeroides, Biochemistry 33 (1994), 1181–1193.CrossRefGoogle Scholar
  17. le Coutre, J. and Gerwert, K.: Kinetic Isotope Effects Reveal an Ice-Like and a Liquid-Phase-type Intramolecular Proton Transfer in Bacteriorhodopsin, FEBS Lett. 398 (1996), 333–336.Google Scholar
  18. Gutman, M. and Nachliel, E.: Time Resolved Dynamics of Proton Transfer in Proteinous Systems, Annu. Rev. Phys. Chem. 48 (1997), 329–356.CrossRefGoogle Scholar
  19. Adelroth, P., Paddock, M.L., Sagle, L.B., Feher, G. and Okamura, M.Y.: Identification of the Proton Pathway in Bacterial Reaction Centers: Both Protons Associated with Reduction of QB to QBH2 Share a Common Entry Point, Proc. Natl. Acad. Sci. U.S.A. 97 (2000), 13086–13091.CrossRefADSGoogle Scholar
  20. Zscherp, C., Schlesinger, R. and Heberle, J.: Time-Resolved FT-IR Spectroscopic Investigation of the pH-Dependent Proton Transfer Reactions in the E194Q Mutant of Bacteriorhodopsin, Biochem. Biophys. Res. Commun. 283 (2001), 57–63.CrossRefGoogle Scholar
  21. Gutman, M., Nachliel, E., Mezer, A. and Noivirt, O.: Gauging of Local Micro-Environment at Protein Water Interface by Time-Resolved Single-Proton Transfer Reactions, Ann. Eur. Acad. Sci. 1 (2003), 75–107.Google Scholar
  22. Nachliel, E. and Gutman, M.: Kinetic Analysis of Proton Transfer Between Reactants Adsorbed to the Same Micelle. The Effect of Proximity on the Rate Constants, Eur. J. Biochem. 143 (1984), 83–88.CrossRefGoogle Scholar
  23. Gutman, M., Nachliel, E., Bamberg, E. and Christensen, B.: Time-Resolved Protonation Dynamics of a Black Lipid Membrane Monitored by Capacitative Currents, Biochim. Biophys. Acta 905 (1987), 390–398.Google Scholar
  24. Checover, S., Marantz, Y., Nachliel, E., Gutman, M., Pfeiffer, M., Tittor, J., Oesterhelt, D. and Dencher, N.A.: Dynamics of the Proton Transfer Reaction on the Cytoplasmic Surface of Bacteriorhodopsin, Biochemistry 40 (2001), 4281–4292.CrossRefGoogle Scholar
  25. Tran-Thi, T.H., Gustavsson, T., Prayer, C., Pommeret, S. and Hynes, J.T.: Primary Ultrafast Events Preceding the Photoinduced Proton Transfer from Pyranine to Water, Chem. Phys. Lett. 329 (2000), 421–430.CrossRefADSGoogle Scholar
  26. Forster, T. and Volker, S.: Kinetics of Proton Transfer Reaction Involving Hydroxypyrene-Trisulfonate in Aqueous Solution by Nanosecond Laser Absorption Spectroscopy, Chem. Phys. Lett. 34 (1975), 1–5.ADSGoogle Scholar
  27. Weller, A.: Excited State Proton Transfer, Prog. React. Kinet. 1 (1961), 198–214.Google Scholar
  28. Gutman, M. and Huppert, D.: Rapid pH and deltamuH+ Jump by Short Laser Pulse, J. Biochem. Biophys. Methods 1 (1979), 9–19.CrossRefGoogle Scholar
  29. Checover, S., Nachliel, E., Dencher, N.A. and Gutman, M.: Mechanism of Proton Entry into the Cytoplasmic Section of the Proton-Conducting Channel of Bacteriorhodopsin, Biochemistry 36 (1997), 13919–13928.CrossRefGoogle Scholar
  30. Marantz, Y., Nachliel, E., Aagaard, A., Brzezinski, P. and Gutman, M.: The Proton Collecting Function of the Inner Surface of Cytochrome C Oxidase from Rhodobacter Sphaeroides, Proc. Natl. Acad. Sci. U.S.A. 95 (1998), 8590–8595.CrossRefADSGoogle Scholar
  31. Cohen, B. and Huppert, D.: Evidence for a Continuous Transition from Nonadiabatic to Adiabatic Proton Transfer Dynamics in Protic Solvents. J. Phys. Chem. A 105 (2001), 2980–2988.Google Scholar
  32. Agalarov, S.C., Prasad, G.S., Funke, P.M., Stout, C.D. and Williamson, J.R.: Structure of the S15,S6,S18-rRNA Complex: Assembly of the 30S Ribosome Central Domain, Science 288 (2000), 107–112.CrossRefADSGoogle Scholar
  33. Lindahl, E., Hess, B. and van der Spoel, D.: Gromacs 3.0: A Package for Molecular Simulation and Trajectory Analysis, J. Mol. Med. 7 (2001), 306–317.Google Scholar
  34. van Gunsteren, W.F. and Berendsen, H.J.C.: Gromos-87 Manual, Biomos BV, Groningen, 1987.Google Scholar
  35. van Buuren, A.R., Marrink, S.J. and Berendsen, H.J.C.: A Molecular Dynamics Study of the Decane/Water Interface, J. Phys. Chem. 97 (1993), 9206–9212.CrossRefGoogle Scholar
  36. Mark, A.E., van Helden, S.P., Smith, P.E., Janssen, L.H.M. and van Gunsteren, W.F.: Convergence Properties of Free Energy Calculations: Alpha-Cyclodextrin Complexes as a Case Study, J. Am. Chem. Soc. 116 (1994), 6293–6302.CrossRefGoogle Scholar
  37. van Buuren, A.R. and Berendsen, H.J.C.: Molecular Dynamics Simulations of the Stability of a 22 Residue Alpha-Helix in Water and 30% Trifluoroethanol, Biopolymers 33 (1993), 1159–1166.CrossRefGoogle Scholar
  38. Liu, H., Muller-Plathe, F. and van Gunsteren, W.F.A.: Force Field for Liquid Dimethyl Sulfoxide and Liquid Proporties of Liquid Dimethyl Sulfoxide Calculated Using Molecular Dynamics Simulation, J. Am. Chem. Soc. 117 (1995), 4363–4366.Google Scholar
  39. Lindahl, M., Svensson, L.A., Liljas, A., Sedelnikova, S.E., Eliseikina, I.A., Fomenkova, N.P., Nevskaya, N., Nikonov, S.V., Garber, M.B. and Muranova, T.A.: Crystal Structure of the Ribosomal Protein S6 from Thermus Thermophilus, EMBO J. 13 (1994), 1249–1254.Google Scholar
  40. Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E.: The Protein Data Bank, Nucleic Acids Res. 28 (2000), 235–242.CrossRefGoogle Scholar
  41. Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F. and Hermans, J.: Interaction Models for Water in Relation to Protein Hydration, Nature 224 (1969), 175–177.Google Scholar
  42. van der Spoel, D. and Berendsen, H.J.C.: Molecular Dynamics Simulations of Leu-Enkephalin in Water and DMSO, Biophys. J. 72 (1997), 2032–2041.Google Scholar
  43. Tieleman, D.P. and Berendsen, H.J.C.: Molecular Dynamics Simulations of a Fully Hydrated Dipalmitoylphosphatidylcholine Bilayer with Different Macroscopic Boundary Conditions and Parameters, J. Chem. Phys. 105 (1996), 4871–4880.CrossRefADSGoogle Scholar
  44. Hess, B., Bekker, H., Berendsen, H.J.C. and Fraaije, J.G.E.M.: LINCS: A Linear Constraint Solver for Molecular Simulations, J. Comp. Chem. 18 (1997), 1463–1472.Google Scholar
  45. Miyamoto, S. and Kollman, P.A.: SETTLE: An Analytical Version of the SHAKE and RATTLE Algorithms for Rigid Water Models, J. Comp. Chem. 13 (1992), 952–962.Google Scholar
  46. Berendsen, H.J.C., Postma, J.P.M., DiNola, A. and Haak, J.R.: Molecular Dynamics with Coupling to an External Bath, J. Chem. Phys. 81 (1984), 3684–3690.CrossRefADSGoogle Scholar
  47. Darden, T., York, D. and Pedersen, L.: Particle Mesh Ewald: An N-log(N) Method for Ewald Sums in Large Systems, J. Chem. Phys. 98 (1993), 10089–10092.CrossRefADSGoogle Scholar
  48. Baker, N.A., Sept, D., Joseph, S., Holst, M.J. and McCammon, J.A.: Electrostatics of Nanosystems: Application to Microtubules and the Ribosome, Proc. Natl. Acad. Sci. U.S.A. 98 (2001), 10037–10041.CrossRefADSGoogle Scholar
  49. Humphrey, W., Dalke, A. and Schulten, K.: VMD: Visual Molecular Dynamics, J. Mol. Gr. 14 (1996), 33–38.Google Scholar
  50. van der Spoel, D., van Maaren, P.J. and Berendsen, H.J.C.: A Systematic Study of Water Models for Molecular Simulation: Derivation of Water Models Optimized for Use with a Reaction Field, J. Chem. Phys. 108 (1998), 10220–10230.CrossRefADSGoogle Scholar
  51. Harned, S.H. and Hildreth, C.L.: The Differential Diffusion Coefficients of Lithium and Sodium Chlorides in Dilute Aqueous Solution at 25 degrees. J. Am. Chem. Soc. 73 (1951), 650–652.Google Scholar
  52. Stokes, R.H.: The Diffusion Coefficients of Eight Uni-Univalent Electrolytes in Aqueous Solution at 25, J. Am. Chem. Soc. 72 (1950), 2243–2247.Google Scholar
  53. Macdonald, P.M. and Seelig, J.: Anion Binding to Neutral and Positively Charged Lipid Membranes, Biochemistry 27 (1988), 6769–6775.Google Scholar
  54. Pandit, S.A., Bostic, D. and Berkowitz, M.L.: Molecular Dynamics Simulation of a Dipalmitoylphosphatidylcholine Bilayer with NaCl, Biophys. J. 84 (2003), 3743–3750.Google Scholar
  55. Froloff, N., Windemuth, A. and Honig, B.: On the Calculation of Binding Free Energies Using Continuum Methods: Application to MHC Class I Protein-Peptide Interactions, Protein Sci. 6 (1997), 1293–1301.CrossRefGoogle Scholar
  56. Miyashita, O., Onuchic, J.N. and Okamura, M.Y.: Continuum Electrostatic Model for the Binding of Cytochrome c2 to the Photosynthesis Reaction Center from Rhodobacter Sphaeroides, Biochemistry 42 (2003), 11651–11660.CrossRefGoogle Scholar
  57. Marantz, Y., Einarsdottir, O.O., Nachliel, E. and Gutman, M.: Proton-Collecting Properties of Bovine Heart Cytochrome C Oxidase: Kinetic and Electrostatic Analysis, Biochemistry 40 (2001), 15086–15097.CrossRefGoogle Scholar
  58. Agmon, N.: The Grotthuss Mechanism, Chem. Phys. Lett. 244 (1995), 456–462.CrossRefADSGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Ran Friedman
    • 1
  • Esther Nachliel
    • 1
  • Menachem Gutman
    • 1
  1. 1.Laser Laboratory for Fast Reactions in Biology, Department of Biochemistry, The George S. Wise Faculty for Life SciencesTel Aviv UniversityTel AvivIsrael

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