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Electrostatic effects in a network of polar and ionizable groups in staphylococcal nuclease.

Baran KL, Chimenti MS, Schlessman JL, Fitch CA, Herbst KJ, Garcia-Moreno BE
J Mol Biol 379 1045-62 (2008)
Cited: 32 times
EuropePMC logo PMID: 18499123

Abstract

His121 and His124 are embedded in a network of polar and ionizable groups on the surface of staphylococcal nuclease. To examine how membership in a network affects the electrostatic properties of ionizable groups, the tautomeric state and the pK(a) values of these histidines were measured with NMR spectroscopy in the wild-type nuclease and in 13 variants designed to disrupt the network. In the background protein, His121 and His124 titrate with pK(a) values of 5.2 and 5.6, respectively. In the variants, where the network was disrupted, the pK(a) values range from 4.03 to 6.46 for His121, and 5.04 to 5.99 for His124. The largest decrease in a pK(a) was observed when the favorable Coulomb interaction between His121 and Glu75 was eliminated; the largest increase was observed when Tyr91 or Tyr93 was substituted with Ala or Phe. In all variants, the dominant tautomeric state at neutral pH was the N(epsilon2) state. At one level the network behaves as a rigid unit that does not readily reorganize when disrupted: crystal structures of the E75A or E75Q variants show that even when the pivotal Glu75 is removed, the overall configuration of the network was unaffected. On the other hand, a few key hydrogen bonds appear to govern the conformation of the network, and when these bonds are disrupted the network reorganizes. Coulomb interactions within the network report an effective dielectric constant of 20, whereas a dielectric constant of 80 is more consistent with the magnitude of medium to long-range Coulomb interactions in this protein. The data demonstrate that when structures are treated as static, rigid bodies, structure-based pK(a) calculations with continuum electrostatics method are not useful to treat ionizable groups in cases where pK(a) values are governed by short-range polar and Coulomb interactions.

Reviews citing this publication (6)

  1. Protein ionizable groups: pK values and their contribution to protein stability and solubility. Pace CN, Grimsley GR, Scholtz JM. J Biol Chem 284 13285-13289 (2009)
  2. Progress in the prediction of pKa values in proteins. Alexov E, Mehler EL, Baker N, Baptista AM, Huang Y, Milletti F, Nielsen JE, Farrell D, Carstensen T, Olsson MH, Shen JK, Warwicker J, Williams S, Word JM. Proteins 79 3260-3275 (2011)
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Articles citing this publication (26)

  1. A summary of the measured pK values of the ionizable groups in folded proteins. Grimsley GR, Scholtz JM, Pace CN. Protein Sci 18 247-251 (2009)
  2. Molecular determinants of the pKa values of Asp and Glu residues in staphylococcal nuclease. Castañeda CA, Fitch CA, Majumdar A, Khangulov V, Schlessman JL, García-Moreno BE. Proteins 77 570-588 (2009)
  3. Rhomboid protease dynamics and lipid interactions. Bondar AN, del Val C, White SH. Structure 17 395-405 (2009)
  4. The pK(a) values of acidic and basic residues buried at the same internal location in a protein are governed by different factors. Harms MJ, Castañeda CA, Schlessman JL, Sue GR, Isom DG, Cannon BR, García-Moreno E B. J Mol Biol 389 34-47 (2009)
  5. Remeasuring HEWL pK(a) values by NMR spectroscopy: methods, analysis, accuracy, and implications for theoretical pK(a) calculations. Webb H, Tynan-Connolly BM, Lee GM, Farrell D, O'Meara F, Søndergaard CR, Teilum K, Hewage C, McIntosh LP, Nielsen JE. Proteins 79 685-702 (2011)
  6. pH-Dependent conformational changes in proteins and their effect on experimental pK(a)s: the case of Nitrophorin 4. Di Russo NV, Estrin DA, Martí MA, Roitberg AE. PLoS Comput Biol 8 e1002761 (2012)
  7. PKAD: a database of experimentally measured pKa values of ionizable groups in proteins. Pahari S, Sun L, Alexov E. Database (Oxford) 2019 baz024 (2019)
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  10. Effective approach for calculations of absolute stability of proteins using focused dielectric constants. Vicatos S, Roca M, Warshel A. Proteins 77 670-684 (2009)
  11. A Histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1. Vercoulen Y, Kondo Y, Iwig JS, Janssen AB, White KA, Amini M, Barber DL, Kuriyan J, Roose JP. Elife 6 e29002 (2017)
  12. Structural plasticity of staphylococcal nuclease probed by perturbation with pressure and pH. Kitahara R, Hata K, Maeno A, Akasaka K, Chimenti MS, Garcia-Moreno E B, Schroer MA, Jeworrek C, Tolan M, Winter R, Roche J, Roumestand C, Montet de Guillen K, Royer CA. Proteins 79 1293-1305 (2011)
  13. Ionization Properties of Histidine Residues in the Lipid Bilayer Membrane Environment. Martfeld AN, Greathouse DV, Koeppe RE. J Biol Chem 291 19146-19156 (2016)
  14. Developing hybrid approaches to predict pKa values of ionizable groups. Witham S, Talley K, Wang L, Zhang Z, Sarkar S, Gao D, Yang W, Alexov E. Proteins 79 3389-3399 (2011)
  15. Using DelPhi capabilities to mimic protein's conformational reorganization with amino acid specific dielectric constants. Wang L, Zhang Z, Rocchia W, Alexov E. Commun Comput Phys 13 13-30 (2013)
  16. Microscopic mechanisms that govern the titration response and pKa values of buried residues in staphylococcal nuclease mutants. Zheng Y, Cui Q. Proteins 85 268-281 (2017)
  17. Application of the Gaussian dielectric boundary in Zap to the prediction of protein pKa values. Word JM, Nicholls A. Proteins 79 3400-3409 (2011)
  18. Translocation and fidelity of Escherichia coli RNA polymerase. Nedialkov YA, Burton ZF. Transcription 4 136-143 (2013)
  19. Protein apparent dielectric constant and its temperature dependence from remote chemical shift effects. An L, Wang Y, Zhang N, Yan S, Bax A, Yao L. J Am Chem Soc 136 12816-12819 (2014)
  20. Using affinity chromatography to engineer and characterize pH-dependent protein switches. Sagermann M, Chapleau RR, DeLorimier E, Lei M. Protein Sci 18 217-228 (2009)
  21. Factors determining electrostatic fields in molecular dynamics simulations of the Ras/effector interface. Ensign DL, Webb LJ. Proteins 79 3511-3524 (2011)
  22. pH dependence of conformational fluctuations of the protein backbone. Richman DE, Majumdar A, García-Moreno E B. Proteins 82 3132-3143 (2014)
  23. Bayesian model aggregation for ensemble-based estimates of protein pKa values. Gosink LJ, Hogan EA, Pulsipher TC, Baker NA. Proteins 82 354-363 (2014)
  24. Functional tuning of the catalytic residue pKa in a de novo designed esterase. Hiebler K, Lengyel Z, Castañeda CA, Makhlynets OV. Proteins 85 1656-1665 (2017)
  25. Entropy Drives the Formation of Salt Bridges in the Protein GB3. Zhang N, Wang Y, An L, Song X, Huang Q, Liu Z, Yao L. Angew Chem Int Ed Engl 56 7601-7604 (2017)
  26. The pH dependence of staphylococcal nuclease stability is incompatible with a three-state denaturation model. Spencer D, Bertrand GM, Stites WE. Biophys Chem 180-181 86-94 (2013)


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