Short, Strong Hydrogen Bonds in the Gas Phase and in Solution:  Theoretical Exploration of pK_a Matching and Environmental Effects on the Strengths of Hydrogen Bonds and Their Potential Roles in Enzymatic Catalysis

Abstract

Short, strong hydrogen bonds are common in charged systems in the gas phase, but the importance of such bonding in enzymatic catalysis has been the subject of considerable controversy. Confusion has arisen about the relationship among bond strength, the "low-barrier" or "no-barrier" nature of the hydrogen bonding, the role of pK a matching, the covalent or electrostatic nature of the bonding, and the role of solvation on the strengths of these types of hydrogen bonds. We have attempted to strip away the "Alice in Wonderland" quality of the definitions in this field by defining, through high-level calculations, when short-strong hydrogen bonds do and do not occur. The strengths and geometries of several types of hydrogen bonds involving anions have been investigated by ab initio quantum mechanical calculations. For a series of enols hydrogen-bonded to enolates, the strengths of the short, strong gas-phase hydrogen bonds are linearly related to the differences between the proton affinities (PA) of the two anions which share the proton. The bond strength is also related to the O‚‚‚O distance between them. There is no discontinuity at ∆PA ) 0, and hydrogen-bonding becomes even stronger in a computational experiment when the PA of the H-bond acceptor exceeds that of the donor. "Low-barrier" hydrogen bonds with single-well minima after inclusion of zero-point energies occur when ∆PA is near 0, but no special stability accrues when the double-well minimum becomes single-well. The maleic/fumaric and mesaconic/citraconic systems studied by Drueckhammer have been investigated computationally. The influence of solvation on hydrogen-bond strength was studied using solvent cavity models. Small increases in dielectric constant from the gas-phase value ( ) 1) rapidly reduce the strengths of charged hydrogen bonds. Short, strong hydrogen bonds occur only with charged systems, and only then in nonpolar ( < 10) environments. Alternative mechanisms are often available to account for enzymatic catalysis; the example of orotidine monophosphate decarboxylase is discussed.

Complexation of Phenol and Thiophenol by Amine N‐Oxides: Isothermal Titration Calorimetry and ab Initio Calculations

“…The hydrogen-bond enthalpy is calculated to be approximately proportional to the inverse fifth power of the hydrogen-bond length: DH~d(H···O) À5.04 . In recent papers [50][51][52] a calculated hydrogen-bond enthalpy proportional to the inverse fifth power of the hydrogen-bond length was also found, in line with a previously made claim [52] that such data should generally fit an inverse power relation ÀDH % f(r Àa ) with a > 3. Recently, we discussed the phenol binding capacity of a number of phosphine oxides and phosphates, and concluded that for phenol recovery from an aqueous environment the liquid phosphine oxide blend Cyanex 923 would be an optimum extractant for SIR applications.…”

Catalytic role of enzymes: Short strong H-bond-induced partial proton shuttles and charge redistributions

“…In the dielectric medium of enzymes, the maximal catalytic effect is obtained in the case of equal pK a s of residues and substrate [these pK a values are quite different from those in bulk water]. This situation is in contrast to single-step reactions wherein a large difference in pK a enhances the reactivity (47,48). The condition of equal pK a s between residues and substrate for the maximal catalytic effect matches the requirement of residues in enzyme to possess equivalent pK a s with the substrate to form the maximal SSHBs (4-7, 15, 23, 24).…”

The crystal structure and mechanism of orotidine 5′-monophosphate decarboxylase

“…The most striking feature of the active site is the absence of acidic residues next to the C2 and the C4 carbonyl groups of the substrate. Specifically, Lys62 (Lys93 in yeast OMP decarboxylase), which was previously proposed to function as the carbonyl activating residue (6,30), is near neither carbonyl group. In addition, there is no nucleophile close to C5 of the pyrimidine.…”