This article examines interactions in enzymes between catalytic and neighboring amino acids and how these interactions facilitate catalysis.
In examples from both natural and designed enzymes, it is shown that increases in catalytic rates may be achieved through elongation of the buffer range of the catalytic residues; such perturbations in the protonation equilibria are, in turn, achieved through enhanced coupling of the protonation equilibria of the active ionizable residues with those of other ionizable residues. The strongest coupling between protonation states for a pair of residues that deprotonate to form an anion (or a pair that accept a proton to form a cation) is achieved when the difference in the intrinsic pKas of the two residues is approximately within 1 pH unit. Thus, catalytic aspartates and glutamates are often coupled to nearby acidic residues. For an anion-forming residue coupled to a cation-forming residue, the elongated buffer range is achieved when the intrinsic pKa of the anion-forming residue is higher than the intrinsic pKa of the (conjugate acid of the) cation-forming residue; therefore, the high pKa, anion-forming residues tyrosine and cysteine make good coupling partners for catalytic lysine residues. For the anion–cation pairs, the optimum difference in intrinsic pKas is a function of the energy of interaction between the residues. For the energy of interaction expressed in units of (ln 10)RT, the optimum difference in intrinsic pKas is within ∼1 pH unit of ε. (publisher abstract modified)