Molecular Dynamics of Hydrogen Bonds in Protein−D₂O:  The Solvent Isotope Effect

Abstract

We suggest that the H-bond in proteins not only mirrors the motion of hydrogen in its own atomistic setting but also finds its origin in the collective environment of the hydrogen bond in a global lattice of surrounding H2O molecules. This water lattice is being perturbed in its optimal entropic configuration by the motion of the H-bond. Furthermore, bonding interaction with the lattice drop the H-bond energy from some 5 kcal/mol for the pure protein in the absence of H2O, to some 1.6 kcal/mol in the presence of the H2O medium. This low value here is determined in a computer experiment involving MD calculations and is a value close to the generally accepted value for biological systems. In accordance with these computer experiments under ambient conditions, the H-bond energy is seriously depressed, hence confirming the subtle effect of the H2O medium directly interacting with the H-bond and permitting a strong fluxional behavior. Furthermore, water produces a very large change in the entropy of activation due to the hydrogen bond breakage, which affects the rate by as much as 2 orders of magnitude. We also observe that there is an entire ensemble of H-bond structures, rather than a single transition state, all of which contribute to this H-bond. Here the model is tested by changing to D2O as the surrounding medium resulting in a substantial solvent isotope effect. This demonstrates the important influence of the environment on the individual hydrogen bond.

Hydrogen Bonding of β-Turn Structure Is Stabilized in D2O

“…For example, proteins possessing mostly β -type structures are preferentially stabilized in D 2 O, while α-helical structures show the opposite trend 6-8. These observations are usually attributed to one of two effects: (1) D 2 O may modulate hydrophobic interactions in proteins or (2) D 2 O may selectively stabilize/destabilize inter- and/or intramolecular hydrogen bonds that are more prevalent in the folded state of proteins 9-17…”

A Single‐Molecule Perspective on the Role of Solvent Hydrogen Bonds in Protein Folding and Chemical Reactions

“…[11] In solution, hydrogen bonds are not rigid, but rather fluxional on a timescale of~50 ps. [12] This fluxional behaviour is due to the low activation energy of hydrogen bond rupturẽ 1-1.5 kcal mol…”

“…Indeed, in the absence of water considerably higher activation energies have been calculated and it has been proposed that diminished fluxional motions would not support many life processes, since physiological temperatures could not lead to rupture and realignment of hydrogen bonds. [12] One model system for exploring the structure and dynamics of hydrogen bonds is that of water (H 2 O) and heavy water, deuterium oxide (D 2 O). [13] The oxygen atom of a water molecule has two lone pairs, each of which can form a hydrogen bond with hydrogen atoms on two other water molecules.…”

Evaluation of Solvent Accessibility Epitopes for Different Dehydrogenase Inhibitors

“…As a consequence, the interaction of DMSO with the protein surface can be more efficient in D 2 O where weaker hydrogen bonds between D 2 O and protein hydrogen atoms are formed. [18] The use of D 2 O will also prevent against loss of magnetization via exchangeable protons of the protein to bulk H 2 O. The crystal structure shows a number of water molecules close to indomethacin and one DMSO molecule close to the ligand binding site (c.f.…”