Variability in the pKa of histidine side‐chains correlates with burial within proteins

Abstract

Acidic pKas of histidines buried within the protein interior are frequently rationalized on the contradictory basis of either polar interactions within the protein or the effects of a hydrophobic environment. To examine these relationships, we surveyed the buried surface area, depth of burial, polar interactions, and crystallographic temperature factors of histidines of known pKa. It has been found that buried environments of histidines do not always result in acidic pKas. Instead, the variability of histidine pKas increases for residues where the majority of the side-chain is buried. Because buried histidines are always found in mixed polar/apolar environments, multiple environmental contributions to pKa values must be considered. However, the quantitative relationships between heterogeneous environments and pKa values are not immediately apparent from the available data.

Lysine acetylation can generate highly charged enzymes with increased resistance toward irreversible inactivation

“…A survey of pK a values of 39 different histidine residues from 13 different proteins (Edgcomb and Murphy 2002) showed that the pK a of imidazole groups (as measured by NMR spectroscopy) differed greatly from the regularly cited (''standard'') value of 6.3 (Thurlkill et al 2006) and ranged from 4.6 (His40 of bovine chymotrypsinogen) to 9.2 (His72 in tyrosine phosphatase). The physicalchemical basis for this variation is not completely understood (Edgcomb and Murphy 2002), but may be due in part to local variations in electrostatic potential. The value of pK a of aspartate-b-CO 2 H and glutamate-g-CO 2 H also vary widely in proteins (García-Moreno et al 1997).…”

Direct Peptide Bioconjugation/PEGylation at Tyrosine with Linear and Branched Polymeric Diazonium Salts

“…41 Due to the high reactivity of tyrosinate/tyrosine residues towards diazonium reagents, the coupling has been reported to occur at pH as low as 4. 37 In the same study the authors reported that over the 4.0-9.0 interval of pH investigated, Tyr analogues had higher reactivity than the corresponding His derivatives.…”

Incorporation of 2,3‐Diaminopropionic Acid into Linear Cationic Amphipathic Peptides Produces pH‐Sensitive Vectors

“…The histidine side chain pKa in proteins is known to vary considerably according to its environment. [19] Titratable histidines in proteins have been identified with a side-chain pKa as high as 9.2 and as low as 4.6. [19] Importantly, Coulombic interactions between neighboring side-chains in space, as predicted for amphipathic peptides [20] , would also be expected to depress the pKa.…”

“…[19] Titratable histidines in proteins have been identified with a side-chain pKa as high as 9.2 and as low as 4.6. [19] Importantly, Coulombic interactions between neighboring side-chains in space, as predicted for amphipathic peptides [20] , would also be expected to depress the pKa. Hence an acidic value for the side-chain pKa of histidine in LAH is neither unexpected nor is it likely to be as a result of either intra-or intermolecular hydrogen bonding.…”