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It is broadly recognized that intramolecular electric fields, produced by the protein scaffold and acting on the active site, facilitate enzymatic catalysis. This field effect can be described by several theoretical models, each of which is intuitive to varying degrees. In this contribution, we show that a fundamental effect of electric fields is to generate electrostatic potentials that facilitate the energetic alignment of reactant frontier orbitals. We apply this model to demystify the impact of electric fields on high-valent iron–oxo heme proteins: catalases, peroxidases, and peroxygenases/monooxygenases. Specifically, we show that this model easily accounts for the observed field-induced changes to the spin distribution within peroxidase active sites and explains the transition between epoxidation and hydroxylation pathways seen in Cytochrome P450 active site models. Thus, for the intuitive interpretation of the chemical effect of the field, the strategy involves analyzing the response of the orbitals of active site fragments, and their energetic alignment. We note that the energy difference between fragment orbitals involved in charge redistribution acts as a measure for the chemical hardness/softness of the reactive complex. This measure, and its sensitivity to electric fields, offers a single parameter model from which to quantitatively assess the effects of electric fields on reactivity and selectivity. Thus, the model provides an additional perspective to describe electrostatic preorganization and offers ways for its manipulation. 

QTAIM coupled to graph neural networks can improve model performance and generalizability. 

A forward-looking perspective on optimizing enzyme design through synergizing electric fields, coordination spheres, and dynamics. 

How does a single amino acid mutation occurring in the blinding disease, Leber’s hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation’s replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.