Including Side Chain Flexibility in Continuum Electrostatic Calculations of Protein Titration

Beroza, Paul; Case, David A.

doi:10.1021/jp9623709

Cited by 122 publications

(151 citation statements)

References 41 publications

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“…Because it subsumes the effects of structural plasticity, the protein dielectric constant has come to be viewed as an adjustable parameter that depends on spatial position within the protein and on the electrostatic property being studied (43). Efforts to incorporate limited side-chain flexibility into electrostatic calculations have been reported [including allowance for hydroxyl rotamer relaxation (34), inclusion of multiple dihedral conformers at titrating sites (35,44), and sampling of multiple protein conformations along a molecular dynamics trajectory (45)(46)(47)(48)(49)], but no methods exist to model the global rearrangements in protein structure that accompany pH changes. The MTK potential was developed specifically to allow an accurate treatment of electrostatics in multicopy sampling calculations that treat global variation in side-chain chemistry and conformation.…”

Section: Discussionmentioning

confidence: 99%

Tanford–Kirkwood electrostatics for protein modeling

Havranek

Harbury²

1999

Proc. Natl. Acad. Sci. U.S.A.

108

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Solvent plays a significant role in determining the electrostatic potential energy of proteins, most notably through its favorable interactions with charged residues and its screening of electrostatic interactions. These energetic contributions are frequently ignored in computational protein design and protein modeling methodologies because they are difficult to evaluate rapidly and accurately. To address this deficiency, we report a revised form of the original Tanford

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Section: Discussionmentioning

confidence: 99%

Tanford–Kirkwood electrostatics for protein modeling

Havranek

Harbury²

1999

Proc. Natl. Acad. Sci. U.S.A.

108

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“…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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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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“…All of the above has motivated the development of algorithms that couple the treatment of conformational flexibility with the exchange of protons between the acidic and basic groups and the solvent. Examples include meanfield models with side-chain flexibility (You and Bashford 1995;Spassov and Bashford 1999;Barth et al 2007), Monte Carlo sampling (Beroza and Case 1996;Georgescu et al 2002), and advanced protocols for molecular-dynamics simulations (for review, see Mongan and Case 2005). Recently an implementation of replica-exchange method in constant pH dynamics (Khandogin and Brooks III 2006) demonstrated an improvement of the accuracy of this class of models that moves the predictions from first principles to a quantitative level.…”

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confidence: 99%

A fast and accurate computational approach to protein ionization

Spassov¹,

Yan²

2008

Protein Science

135

129

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We report a very fast and accurate physics-based method to calculate pH-dependent electrostatic effects in protein molecules and to predict the pK values of individual sites of titration. In addition, a CHARMm-based algorithm is included to construct and refine the spatial coordinates of all hydrogen atoms at a given pH. The present method combines electrostatic energy calculations based on the Generalized Born approximation with an iterative mobile clustering approach to calculate the equilibria of proton binding to multiple titration sites in protein molecules. The use of the GBIM (Generalized Born with Implicit Membrane) CHARMm module makes it possible to model not only water-soluble proteins but membrane proteins as well. The method includes a novel algorithm for preliminary refinement of hydrogen coordinates. Another difference from existing approaches is that, instead of monopeptides, a set of relaxed pentapeptide structures are used as model compounds. Tests on a set of 24 proteins demonstrate the high accuracy of the method. On average, the RMSD between predicted and experimental pK values is close to 0.5 pK units on this data set, and the accuracy is achieved at very low computational cost. The pH-dependent assignment of hydrogen atoms also shows very good agreement with protonation states and hydrogen-bond network observed in neutron-diffraction structures. The method is implemented as a computational protocol in Accelrys Discovery Studio and provides a fast and easy way to study the effect of pH on many important mechanisms such as enzyme catalysis, ligand binding, protein-protein interactions, and protein stability.

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Including Side Chain Flexibility in Continuum Electrostatic Calculations of Protein Titration

Cited by 122 publications

References 41 publications

Tanford–Kirkwood electrostatics for protein modeling

Tanford–Kirkwood electrostatics for protein modeling

Defining the Role of Salt Bridges in Protein Stability

A fast and accurate computational approach to protein ionization

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