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Modeling the Influence of Salt on the Hydrophobic Effect and Protein Fold Stability

Published online by Cambridge University Press:  03 June 2015

Mihir S. Date  and
Brian N. Dominy
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Abstract

Salt influences protein stability through electrostatic mechanisms as well as through nonpolar Hofmeister effects. In the present work, a continuum solvation based model is developed to explore the impact of salt on protein stability. This model relies on a traditional Poisson-Boltzmann (PB) term to describe the polar or electrostatic effects of salt, and a surface area dependent term containing a salt concentration dependent microscopic surface tension function to capture the non-polar Hofmeister effects. The model is first validated against a series of cold-shock protein variants whose salt-dependent protein fold stability profiles have been previously determined experimentally. The approach is then applied to HIV-1 protease in order to explain an experimentally observed enhancement in stability and activity at high (1M) NaCl concentration. The inclusion of the salt-dependent non-polar term brings the model into quantitative agreement with experiment, and provides the basis for further studies into the impact of ionic strength on protein structure, function, and evolution.

Keywords

87.15.K-87.15.-vElectrostatic stabilityhydrophobic effecthalophilecold shock proteinHIV-1 protease
Type
Research Article
Information
Communications in Computational Physics , Volume 13 , Issue 1 , January 2013 , pp. 90 - 106
Copyright
Copyright © Global Science Press Limited 2013

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References

[1]Schildkraut, C. and Lifson, S., Dependence of the melting temperature of DNA on salt con-centration, Biopolymers, 3 (1965), 195–208.Google Scholar
[2]Zaccai, G. and Eisenberg, H., Halophilic proteins and the influence of solvent on protein stabilization, Trends in Biochemical Sciences, 15 (1990), 333–337.Google Scholar
[3]Rao, J. K. M. and Argos, P., Structural stability of halophilic proteins, Biochemistry, 20 (1981), 6536–6543.Google Scholar
[4]Goedken, E. R. and Marqusee, S., Co-crystal of escherichia coli rnase hi with mn2+ ions reveals two divalent metals bound in the active site, Journal of Biological Chemistry, 276 (2001), 7266–7271.Google Scholar
[5]Record, M. T. Jr, Zhang, W. and Anderson, C. F., Analysis of effects of salts and uncharged solutes on protein and nucleic acid equilibria and processes: A practical guide to recognizing and interpreting polyelectrolyte effects, hofmeister effects, and osmotic effects of salts, in: Frederic, D. S. E., Richards, M. and Peter, S. K. (Eds.) Advances in Protein Chemistry, Academic Press, 1998, pp. 281–353.Google Scholar
[6]Elcock, A. H. and McCammon, J. A., Electrostatic contributions to the stability of halophilic proteins, Journal of Molecular Biology, 280 (1998), 731–748.Google Scholar
[7]Baldwin, R. L., How hofmeister ion interactions affect protein stability, Biophysical Journal, 71 (1996), 2056–2063.Google Scholar
[8]Im, W., Beglov, D. and Roux, B., Continuum solvation model: Computation of electrostatic forces from numerical solutions to the poisson-boltzmann equation, Computer Physics Communications, 111 (1998), 59–75.Google Scholar
[9]Nicholls, A. and Honig, B., A rapid finite difference algorithm, utilizing successive overrelaxation to solve the poisson-boltzmann equation, Journal of Computational Chemistry, 12 (1991), 435–445.Google Scholar
[10]Bashford, D. and Case, D. A., Generalized born models of macromolecular solvation effects, Annual Review of Physical Chemistry, 51 (2000), 129–152.CrossRefGoogle ScholarPubMed
[11]Sitkoff, D., Sharp, K. A. and Honig, B., Accurate calculation of hydration free energies using macroscopic solvent models, The Journal of Physical Chemistry, 98 (1994), 1978–1988.Google Scholar
[12]Sitkoff, D., Sharp, K. A. and Honig, B., Correlating solvation free energies and surface tensions of hydrocarbon solutes, Biophysical Chemistry, 51 (1994), 397–409.Google Scholar
[13]Wagoner, J. A. and Baker, N. A., Assessing implicit models for nonpolar mean solvation forces: The importance of dispersion and volume terms, Proceedings of the National Academy of Sciences, 103 (2006), 8331–8336.Google Scholar
[14]Gallicchio, E., Kubo, M. M. and Levy, R. M., Enthalpy-entropy and cavity decomposition of alkane hydration free energies: Numerical results and implications for theories of hydrophobic solvation, The Journal of Physical Chemistry B, 104 (2000), 6271–6285.Google Scholar
[15]Huang, X., Margulis, C. J. and Berne, B. J., Dewetting-induced collapse of hydrophobic particles, Proceedings of the National Academy of Sciences of the United States of America, 100 (2003), 11953–11958.Google Scholar
[16]Szeltner, Z. and Polgár, L., Conformational stability and catalytic activity of hiv-1 protease are both enhanced at high salt concentration, Journal of Biological Chemistry, 271 (1996), 5458–5463.Google Scholar
[17]Perl, D. and Schmid, F. X., Electrostatic stabilization of a thermophilic cold shock protein, Journal of Molecular Biology, 313 (2001), 343–357.Google Scholar
[18]Schindelin, H., Marahiel, M. A. and Heinemann, U., Universal nucleic acid-binding domain revealed by crystal structure of the b. Subtilis major cold-shock protein, Nature, 364 (1993), 164–168.Google Scholar
[19]Mueller, U., Perl, D., Schmid, F. X. and Heinemann, U., Thermal stability and atomic-resolution crystal structure of the bacillus caldolyticus cold shock protein, Journal of Molecular Biology, 297 (2000), 975–988.Google Scholar
[20]Brooks, B., Bruccoleri, R., Olafson, B., States, D., Swaminathan, S. and Karplus, M., Charmm: A program for macromolecular energy, minimization, and dynamics calculations, Journal of Computational Chemistry, 4 (1983), 187–217.Google Scholar
[21]Sanchez, R and S, S., Comparative protein structure modeling. Introduction and practical examples with modeller, Methods in Molecular Biology, 143 (2000), 97–129.Google Scholar
[22]Spinelli, S., Liu, Q. Z., Alzari, P. M., Hirel, P. H. and Poljak, R. J., The three-dimensional structure of the aspartyl protease from the hiv-1 isolate bru, Biochimie, 73 (1991), 1391–1396.Google Scholar
[23]Lapatto, R., Blundell, T., Hemmings, A., Overington, J., Wilderspin, A., Wood, S., Merson, J. R., Whittle, P. J., Danley, D. E., Geoghegan, K. F., Hawrylik, S. J., Lee, S. E., Scheld, K. G. and Hobart, P. M., X-ray analysis of hiv-1 proteinase at 2.7 [angst] resolution confirms structural homology among retroviral enzymes, Nature, 342 (1989), 299–302.Google Scholar
[24]Wang, W. and Kollman, P. A., Free energy calculations on dimer stability of the hiv protease using molecular dynamics and a continuum solvent model, Journal of Molecular Biology, 303 (2000), 567–582.Google Scholar
[25]Wiley, A. P., Williams, S. L. and Essex, J. W., Conformational motions of hiv-1 protease identified using reversible digitally filtered molecular dynamics, Journal of Chemical Theory and Computation, 5 (2009), 1117–1128.Google Scholar
[26]Smith, R., Brereton, I. M., Chai, R. Y. and Kent, S. B. H., Ionization states of the catalytic residues in hiv-1 protease, Nature Structural & Molecular Biology, 3 (1996), 946–950.Google Scholar
[27]Dominy, B. N., Perl, D., Schmid, F. X. and Brooks, C. L., The effects of ionic strength on protein stability: The cold shock protein family, Journal of Molecular Biology, 319 (2002), 541–554.Google Scholar
[28]Todd, M. J., Semo, N. and Freire, E., The structural stability of the hiv-1 protease, Journal of Molecular Biology, 283 (1998), 475–488.Google Scholar
[29]Levy, Y., Caflisch, A., Onuchic, J. N. and Wolynes, P. G., The folding and dimerization of hiv-1 protease: Evidence for a stable monomer from simulations, Journal of Molecular Biology, 340 (2004), 67–79.Google Scholar
[30]Yang, A. and Honig, B., Structural origins of ph and ionic strength effects on protein stability: Acid denaturation of sperm whale apomyoglobin, Journal of Molecular Biology, 237 (1994), 602–614.Google Scholar
[31]Schutz, C. N. and Warshel, A., What are the dielectric “Constants” Of proteins and how to validate electrostatic models?, Proteins: Structure, Function, and Genetics, 44 (2001), 400–417.Google Scholar
[32]Elcock, A. H., Realistic modeling of the denatured states of proteins allows accurate calculations of the ph-dependence of protein stability, Journal of Molecular Biology, 294 (1999), 1051–1062.Google Scholar
[33]Antosiewicz, J., McCammon, J. A. and Gilson, M. K., Prediction of ph-dependent properties of proteins, Journal of Molecular Biology, 238 (1994), 415–436.Google Scholar
[34]Zhou, H.-X., Interactions of macromolecules with salt ions: An electrostatic theory for the hofmeister effect, Proteins: Structure, Function, and Bioinformatics, 61 (2005), 69–78.Google Scholar
[35]Zhou, H.-X. and Dong, F., Electrostatic contributions to the stability of a thermophilic cold shock protein, Biophysical Journal, 84 (2003), 2216–2222.Google Scholar
[36]Ariyama, K., A theory of surface tension of debye-huckel electrolyte, Bulletin of the Chemical Society of Japan, 12 (1937), 32–37.Google Scholar
[37]Onsager, L. and Samaras, N., The surface tension of debye-huiickel electrolyte, The Journal of Chemical Physics, 2 (1934), 528–536.Google Scholar
[38]Belton, J., The theory of surface tension of electrolytes, Transactions of the Faraday Society, 33 (1937), 1449–1454.Google Scholar
[39]Rashin, A. A. and Bukatin, M. A., Continuum based calculations of hydration entropies and the hydrophobic effect, The Journal of Physical Chemistry, 95 (1991), 2942–2944.Google Scholar
[40]Sharp, K., Nicholls, A., Fine, R. and Honig, B., Reconciling the magnitude of the microscopic and macroscopic hydrophobic effects, Science, 252 (1991), 106–109.Google Scholar
[41]Sharp, K. A., Nicholls, A., Friedman, R. and Honig, B., Extracting hydrophobic free energies from experimental data: Relationship to protein folding and theoretical models, Biochemistry, 30 (1991), 9686–9697.Google Scholar
[42]Ben-Naim, A., Solvation thermodynamics of nonionic solutes, The Journal of Chemical Physics, 81 (1984), 2016–2027.Google Scholar
[43]Simonson, T. and Bruenger, A. T., Solvation free energies estimated from macroscopic continuum theory: An accuracy assessment, The Journal of Physical Chemistry, 98 (1994), 4683–4694.Google Scholar
[44]Leroy, P., Lassin, A., Azaroual, M. and Andre, L., Predicting the surface tension of aqueous 1:1 electrolyte solutions at high salinity, Geochimica et Cosmochimica Acta, 74 (2010), 5427–5442.Google Scholar
[45]Arakawa, T. and Timasheff, S. N., Preferential interactions of proteins with salts in concentrated solutions, Biochemistry, 21 (1982), 6545–6552.Google Scholar
[46]Perl, D., Mueller, U., Heinemann, U. and Schmid, F. X., Two exposed amino acid residues confer thermostability on a cold shock protein, Nature Structural Biology, 7 (2000), 380–383.Google Scholar
[47]Polgár, L., Szeltner, Z. and Boros, I., Substrate-dependent mechanisms in the catalysis of human immunodeficiency virus protease, Biochemistry, 33 (1994), 9351–9357.Google Scholar
[48]Nicholson, L. K., Yamazaki, T., Torchia, D. A., Grzesiek, S., Bax, A., Stahl, S. J., Kaufman, J. D., Wingfield, P. T., Lam, P. Y. S., Jadhav, P. K., Hodge, C. N., Domaille, P. J. and Chang, C.-H., Flexibility and function in hiv-1 protease, Nature Structural & Molecular Biology, 2 (1995), 274–280.Google Scholar
[49]Scott, W. R. P. and Schiffer, C. A., Curling of flap tips in hiv-1 protease as a mechanism for substrate entry and tolerance of drug resistance, Structure (London, England: 1993), 8 (2000), 1259–1265.Google Scholar
[50]Perryman, A. L., Lin, J.-H. and McCammon, J. A., Hiv-1 protease molecular dynamics of a wild-type and of the v82f/i84v mutant: Possible contributions to drug resistance and a potential new target site for drugs, Protein Science, 13 (2004), 1108–1123.Google Scholar