Improved Structure-Based Histidine p<i>K</i>_a Prediction for pH-Responsive Protein Design.

ABSTRACT: The near neutral pK_a of histidine is commonly exploited to engineer pH-sensitive biomolecules. For example, histidine mutations introduced in the complementarity-determining region (CDR) of therapeutic antibodies can enhance selectivity for antigens in the acidic microenvironment of solid tumors or increase dissociation rates in the acidic early endosomes of cells. While solvent-exposed histidines typically have a pK_a near 6.5, interacting histidines can experience pK_a shifts of up to 4 pH units in either direction, making histidine one of the most variable titratable residues. To assist in selecting potential histidine mutation sites, pK_a prediction software should achieve an accuracy significantly better than the cur

SUBMITTER: Hogues H 

PROVIDER: S-EPMC11815838 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature