Hydrogen tunnelling in enzyme-catalysed H-transfer reactions: flavoprotein and quinoprotein systems

Abstract

It is now widely accepted that enzyme-catalysed C-H bond breakage occurs by quantum mechanical tunnelling. This paradigm shift in the conceptual framework for these reactions away from semiclassical transition state theory (TST, i.e. including zero-point energy, but with no tunnelling correction) has been driven over the recent years by experimental studies of the temperature dependence of kinetic isotope effects (KIEs) for these reactions in a range of enzymes, including the tryptophan tryptophylquinone-dependent enzymes such as methylamine dehydrogenase and aromatic amine dehydrogenase, and the flavoenzymes such as morphinone reductase and pentaerythritol tetranitrate reductase, which produced observations that are also inconsistent with the simple Bell-correction model of tunnelling. However, these data-especially, the strong temperature dependence of reaction rates and the variable temperature dependence of KIEs-are consistent with other tunnelling models (termed full tunnelling models), in which protein and/or substrate fluctuations generate a configuration compatible with tunnelling. These models accommodate substrate/protein (environment) fluctuations required to attain a configuration with degenerate nuclear quantum states and, when necessary, motion required to increase the probability of tunnelling in these states. Furthermore, tunnelling mechanisms in enzymes are supported by atomistic computational studies performed within the framework of modern TST, which incorporates quantum nuclear effects.

Preservation of Protein Dynamics in Dihydrofolate Reductase Evolution

“…The advantage of this experimental method is that the temperature dependence of KIEs is highly sensitive to the changes in the hydrogen donor and acceptor distance (DAD), which can modulate the degree of the nuclear wave function overlap between the donor and acceptor states of the hydride being transferred (27,30). As suggested by several phenomenological models, referred to here as Marcus-like models, temperature-independent KIEs indicate a short and narrow distribution of DADs, whereas temperature-dependent KIEs are associated with longer and broader DAD distributions with lower fluctuation frequency (27,(31)(32)(33)(34). QM/MM calculations have confirmed that the DAD is the dominant factor in determining the temperature dependence of the KIE in ecDHFR (6,7,10,28).…”

The Hormesis of Thinking: A Deeper Quantum Thermodynamic Perspective?

“…In fact it has been long thought that electrons can move along enzymes in a manner similar to that observed in semiconductors [35], which may be due to quantum tunnelling [36]. It also appears that enzymes also utilise proton tunnelling [37]. Life may use thermal vibrations to pump coherence, which results in a phenomenon known as quantum beating.…”

Wide-dynamic-range kinetic investigations of deep proton tunnelling in proteins

“…4) and slower time scales 5,31,32 and are often attributed to conformational (classical) distributions of the D-A distance 4,5,7,[33][34][35] . Other approaches 12,27,36 factor out and quantize the D-A vibration (~100 fs), as well as the much higher frequency (~10 fs) vibrational mode of the tunneling particle, which is a common feature in all analytical models (see Supplementary Discussion 4).…”