Role of the protein side‐chain fluctuations on the strength of pair‐wise electrostatic interactions: Comparing experimental with computed p<i>K<sub>a</sub></i>s

Alexov, Emil

doi:10.1002/prot.10265

Cited by 65 publications

(61 citation statements)

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“…Various protocols combining calculations of ionization equilibria with simulated protein flexibility have been elaborated. In different approaches, the considered structural changes rank from involving only polar hydrogen atoms (18,19,30,33), to side-chain fluctuations (31,32,34,35,38), to global structural motions (6,23,28,(39)(40)(41)(42). Overall, pK values from MD ensemble averages were closer to the experimental values in most cases.…”

Section: Conformational Flexibilitymentioning

confidence: 85%

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Defining the Role of Salt Bridges in Protein Stability

Jelesarov

Karshikoff

2008

Methods in Molecular Biology

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Running head: Salt bridges and protein stability 2 (i) SummaryAlthough the energetic balance of forces stabilizing proteins has been established qualitatively over the last decades, quantification of the energetic contribution of particular interactions still poses serious problems. The reasons are the strong cooperativity and the interdependence of noncovalent interactions. Salt bridges are a typical example. One expects that ionizable side chains frequently form ion pairs in innumerable crystal structures. Since electrostatic attraction between opposite charges is strong per se, salt bridges can intuitively be regarded as an important factor stabilizing the native structure. Is that really so? In this chapter we critically reassess the available methods to delineate the role of electrostatic interactions and salt bridges to protein stability, and discuss the progress and the obstacles in this endeavor. The basic problem is that formation of salt bridges depends on the ionization properties of the participating groups, which is significantly influenced by the protein environment. Furthermore, salt bridges experience thermal fluctuations, continuously break and re-form, and their lifespan in solution is governed by the flexibility of the protein. Finally, electrostatic interactions are long-range and might be significant in the unfolded state, thus seriously influencing the energetic profile. Elimination of salt bridges by protonation/deprotonation at extreme pH or by mutation provides only rough energetic estimates, since there is no way to account for the non-additive response of the protein moiety. From what we know so far, the strength of electrostatic interactions is strongly contextdependent, yet it is unlikely that salt bridges are dominant factors governing protein stability.Nevertheless, proteins from thermophiles and hyperthermophiles exhibit more, and frequently networked, salt bridges than proteins from the mesophilic counterparts. Increasing the thermal (not the thermodynamic) stability of proteins by optimization of charge-charge interactions is a good example for an evolutionary solution utilizing physical factors.(ii) Keywords: electrostatic interactions, salt bridge, protein stability, thermal stability, denatured state, pK, protein unfolding 3

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Section: Conformational Flexibilitymentioning

confidence: 85%

“…A large number of studies have focused on description and analysis of local conformational flexibility effects on ionization equilibria of individual titratable sites (18,19,(30)(31)(32)(33)(34)(35). For example, the conformational space defined by the side chain torsion angles can be systematically explored (31).…”

Section: Conformational Flexibilitymentioning

confidence: 99%

Defining the Role of Salt Bridges in Protein Stability

Jelesarov

Karshikoff

2008

Methods in Molecular Biology

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“…high) dielectric constant, therefore the physical correctness of this model might be not certain. Alexov [15] has noted the fact that x-ray crystallography does not identify many buried waters in proteins and therefore he considered vdW models to be not correct. But one might argue that the vdW model is consistent with ascribing protein interior slightly higher dielectric constant than that would result from only electronic polarizability, due to fluctuations in the conformation as a response to the electric field.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Poisson–Boltzmann model analysis of binding mRNA cap analogues to the translation initiation factor eIF4E

Szklarczyk

Zuberek

Antosiewicz

2009

Biophysical Chemistry

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractThe electrostatic free energy of binding of two analogues of the 5'-mRNA cap, differing in size and electric charge, to the wild type and mutated eukaryotic initiation factor eIF4E was computed using the finite difference solutions to the Poisson-Boltzmann equation. Two definitions of the solute-solvent dielectric boundary were used: van der Waals model, solvent exclusion (SE) model. The computed electrostatic energies were supplemented by estimations of the non polar and entropic contributions. A comparison with experimental data for the investigated systems was done. It appears that the SE model with additional contribution fits experimental findings better than the van der Waals model does.

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“…17 Alternative approaches to account for the conformational flexibility of proteins include the use of sets of NMR conformers 18 or ensembles of structures generated by MD simulations. 6,19,20 The combination of MD and pK calculations results in an overall improvement of the theoretically predicted pK values. However, discrepancies between experimental and calculated pK values remain most often for groups buried in the protein interior.…”

Section: Methodsmentioning

confidence: 87%

Electrostatic contribution to the thermodynamic and kinetic stability of the homotrimeric coiled coil Lpp‐56: A computational study

et al. 2008

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Electrostatic contribution to the thermodynamic and kinetic stability of the homotrimeric coiled coil Lpp-56: A computational study 2006;45:8931-8939). The unfolding rate constant measured using GdmCl as the denaturing agent, though extremely low, was substantially higher than that obtained on the basis of thermal unfolding. If this large difference arises from the effect of screening of electrostatic interactions induced by GdmCl, electrostatic interactions would appear to be an important factor determining the unusual properties of Lpp-56. We present here a computational analysis of the electrostatic properties of Lpp-56 combining molecular dynamics simulations and continuum pK calculations. The pH-dependence of the unfolding free energy is predicted in good agreement with the experimental data: the change in DeltaG between pH 3 and pH 7 is approximately 60 kJ mol(-1). The results suggest that the difference in the stability of the protein observed using different experimental methods is mainly because of the effect of the reduction of electrostatic interactions when the salt (GdmCl) concentration increases. We also find that the occupancy of the interhelical salt bridges is unusually high. We hypothesize that electrostatic interactions, and the interhelical salt bridges in particular, are an important factor determining the low unfolding rate of Lpp-56. is an attractive object of biophysical investigation in several aspects. It is a homotrimeric, parallel coiled coil, a class of coiled coils whose stability and folding have been studied only occasionally. Lpp-56 possesses unique structural properties and exhibits extremely low rates of folding and unfolding. It is natural to ask how the specificity of the structure determines the extraordinary physical chemical properties of interactions would appear to be an important factor determining the unusual properties of Lpp-56. We present here a computational analysis of the electrostatic properties of Lpp-56 combining molecular dynamics simulations and continuum pK calculations. The results suggest that the difference in the stability of the protein observed using different experimental methods is mainly due to effect of the reduction of electrostatic interactions when the salt (GdmCl) concentration increases. We also find that the occupancy of the interhelical salt bridges is unusually high. We hypothesize that electrostatic interactions, and the interhelical salt bridges in particular, are an important factor determining the low unfolding rate of Lpp-56.

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Role of the protein side‐chain fluctuations on the strength of pair‐wise electrostatic interactions: Comparing experimental with computed pK_as

Cited by 65 publications

References 50 publications

Defining the Role of Salt Bridges in Protein Stability

Defining the Role of Salt Bridges in Protein Stability

Poisson–Boltzmann model analysis of binding mRNA cap analogues to the translation initiation factor eIF4E

Electrostatic contribution to the thermodynamic and kinetic stability of the homotrimeric coiled coil Lpp‐56: A computational study

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Role of the protein side‐chain fluctuations on the strength of pair‐wise electrostatic interactions: Comparing experimental with computed pKas

Cited by 65 publications

References 50 publications

Defining the Role of Salt Bridges in Protein Stability

Defining the Role of Salt Bridges in Protein Stability

Poisson–Boltzmann model analysis of binding mRNA cap analogues to the translation initiation factor eIF4E

Electrostatic contribution to the thermodynamic and kinetic stability of the homotrimeric coiled coil Lpp‐56: A computational study

Contact Info

Product

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Role of the protein side‐chain fluctuations on the strength of pair‐wise electrostatic interactions: Comparing experimental with computed pK_as