Pinpointing Dynamic Coupling in Enzymes for Efficient Drug Design

Loveridge, E. Joel; Allemann, Rudolf Konrad

doi:10.4155/fsoa.2015.0017

Cited by 1 publication

(1 citation statement)

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“…However, these studies show different effects of isotopic substitution depending on the enzymatic system. Beyond assessing the importance of protein dynamics in enzyme catalysis − heavy enzyme studies have also been used in the development of inhibitors for pharmaceutical applications as well. , Nevertheless, further investigation is vital to obtain a comprehensive understanding of the correlation between altered fast protein dynamics and the catalyzed reaction along with other effects of isotopic substitution on enzyme catalysis.…”

Section: Introductionmentioning

confidence: 99%

Protein Mass Effects on Formate Dehydrogenase

et al. 2017

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Isotopically labeled enzymes (denoted as “heavy” or “Born Oppenheimer” enzymes) have been used to test the role of protein dynamics in catalysis. The original idea was that the protein's higher mass would reduce the frequency of its normal-modes without altering its electrostatics. Heavy enzymes have been used to test if the vibrations in the native enzyme are coupled to the chemistry it catalyzes, and different studies have resulted in ambiguous findings. Here the temperature-dependence of intrinsic kinetic isotope effects of the enzyme formate dehydrogenase is used to examine the distribution of H-donor to H-acceptor distance as a function of the protein's mass. The protein dynamics are altered in the heavy enzyme to diminish motions that determine the transition state sampling in the native enzyme, in accordance with a Born Oppenheimer-like effect on bond activation. Findings of this work suggest components related to fast frequencies that can be explained by Born-Oppenheimer enzyme hypothesis (vibrational) and also slower timescale events that are non-Born-Oppenheimer in nature (electrostatic), based on evaluations of protein mass dependence of donor-acceptor-distance and forward commitment to catalysis along with steady state and single turnover measurements. Together, the findings suggest that the mass modulation affected both local, fast, protein vibrations associated with the catalyzed chemistry, and the protein's macromolecular electrostatics at slower timescales, i.e., both Born Oppenheimer and non-Born Oppenheimer effects are observed. Comparison to previous studies leads to the conclusion that isotopic labeling of the protein may have different effects on different systems, however making heavy enzyme studies a very exciting technique for exploring the dynamics link to catalysis in proteins.

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