|Title||Understanding the pK(a) of redox cysteines: the key role of hydrogen bonding.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Roos, G., N. Foloppe, and J. Messens|
|Journal||Antioxid Redox Signal|
|Date Published||2013 Jan 01|
|Type of Article||redox|
|Keywords||Algorithms, Animals, Cysteine, Humans, Hydrogen Bonding, Hydrogen-Ion Concentration, Models, Chemical, Oxidation-Reduction, Protein Structure, Secondary, Proteins, Thermodynamics|
Many cellular functions involve cysteine chemistry via thiol-disulfide exchange pathways. The nucleophilic cysteines of the enzymes involved are activated as thiolate. A thiolate is much more reactive than a neutral thiol. Therefore, determining and understanding the pK(a)s of functional cysteines are important aspects of biochemistry and molecular biology with direct implications for redox signaling. Here, we describe the experimental and theoretical methods to determine cysteine pK(a) values, and we examine the factors that control these pK(a)s. Drawing largely on experience gained with the thioredoxin superfamily, we examine the roles of solvation, charge-charge, helix macrodipole, and hydrogen bonding interactions as pK(a)-modulating factors. The contributions of these factors in influencing cysteine pK(a)s and the associated chemistry, including the relevance for the reaction kinetics and thermodynamics, are discussed. This analysis highlights the critical role of direct hydrogen bonding to the cysteine sulfur as a key factor modulating the equilibrium between thiol S-H and thiolate S(-). This role is easily understood intuitively and provides a framework for biochemical functional insights.
|Alternate Journal||Antioxid. Redox Signal.|
Understanding the pK(a) of redox cysteines: the key role of hydrogen bonding.