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Defining the role of salt bridges in protein stability


Jelesarov, I; Karshikoff, A (2009). Defining the role of salt bridges in protein stability. In: Shriver, J W. Protein structures, stability and interactions. Totowa, NJ: Humana Press (Springer books), Chapter 10.

Abstract

Although 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 nonadditive response of the protein moiety. From what we know so far, the strength of electrostatic interactions is strongly context-dependent, 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.

Although 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 nonadditive response of the protein moiety. From what we know so far, the strength of electrostatic interactions is strongly context-dependent, 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.

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Additional indexing

Item Type:Book Section, not refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:Electrostatic interactions - salt bridge - protein stability - thermal stability - denatured state - pK - protein unfolding
Language:English
Date:1 November 2009
Deposited On:23 Sep 2008 09:04
Last Modified:05 Apr 2016 12:28
Publisher:Humana Press (Springer books)
Series Name:Methods in Molecular Biology
Number:490
ISBN:978-1-58829-954-3 (Print) 978-1-59745-367-7 (Online)
Publisher DOI:10.1007/978-1-59745-367-7
Related URLs:http://www.springerlink.com/content/978-1-58829-954-3
Permanent URL: http://doi.org/10.5167/uzh-3726

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