Models for Strong Interactions in Proteins and Enzymes. 1. Enhanced Acidities of Principal Biological Hydrogen Donors

Article abstract of DOI:10.1021/ja00218a013

The acid dissociation energies of several key biological hydrogen donors are found to fall into a narrow range, ΔH^o_acid=352-355 kcal/mol.The strong acidities of these donor groups enhance the hydrogen bond strengths involved in the protein α-helix, imidazole enzyme centers and DNA.Specifically, the peptide link is modeled by the dipeptide analogue CH3CO-Ala-OCH3.Its acidity is strengthened, i.e. ΔH^o_acid is decreased by 8 kcal/mol compared with other amides, due to electrostatic stabilization by the second carbonyl in the peptide -CON^-CH(CH3)CO- grouping.The acidity of imidazole is also strengthened by 8 kcal/mol compared with that of the parent molecule, pyrrole, primarily due to resonance stabilization of the ion.Hydrogen donor NH2 groups of adenine and cytosine are modeled by 4-aminopyrimidine, and the acidity of this amine group is strengthened by ring aza substitution.An intrinsic acidity optimized for hydrogen bonding strength therefore emerges as a common property of the diverse hydrogen donors in the protein α-helix, enzymes and DNA.This property may therefore be in part responsible for the natural selection of these molecules as principal biological hydrogen donors.