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1. Electric fields imbue enzyme reactivity by aligning active site fragment orbitals

   https://doi.org/10.1073/pnas.2411976121  

   Eberhart, Mark E; Wilson, Timothy R; Jones, Travis E; Alexandrova, Anastassia N (October 2024, Proceedings of the National Academy of Sciences)

   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. 

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2. A Free Energy Decomposition Analysis: Insight into Binding Thermodynamics from Absolutely Localized Molecular Orbitals

   https://doi.org/10.1021/acs.jpclett.3c01397  

   Talbot, Justin J.; Chakraborty, Romit; Shen, Hengyuan; Head-Gordon, Martin (June 2023, The Journal of Physical Chemistry Letters)
3. Probing radical–molecule interactions with a second generation energy decomposition analysis of DFT calculations using absolutely localized molecular orbitals

   https://doi.org/10.1039/d0cp01933j  

   Mao, Yuezhi; Levine, Daniel S.; Loipersberger, Matthias; Horn, Paul R.; Head-Gordon, Martin (June 2020, Physical Chemistry Chemical Physics)

   Intermolecular interactions between radicals and closed-shell molecules are ubiquitous in chemical processes, ranging from the benchtop to the atmosphere and extraterrestrial space. While energy decomposition analysis (EDA) schemes for closed-shell molecules can be generalized for studying radical–molecule interactions, they face challenges arising from the unique characteristics of the electronic structure of open-shell species. In this work, we introduce additional steps that are necessary for the proper treatment of radical–molecule interactions to our previously developed unrestricted Absolutely Localized Molecular Orbital (uALMO)-EDA based on density functional theory calculations. A “polarize-then-depolarize” (PtD) scheme is used to remove arbitrariness in the definition of the frozen wavefunction, rendering the ALMO-EDA results independent of the orientation of the unpaired electron obtained from isolated fragment calculations. The contribution of radical rehybridization to polarization energies is evaluated. It is also valuable to monitor the wavefunction stability of each intermediate state, as well as their associated spin density profiles, to ensure the EDA results correspond to a desired electronic state. These radical extensions are incorporated into the “vertical” and “adiabatic” variants of uALMO-EDA for studies of energy changes and property shifts upon complexation. The EDA is validated on two model complexes, H 2 O⋯˙F and FH⋯˙OH. It is then applied to several chemically interesting radical–molecule complexes, including the sandwiched and T-shaped benzene dimer radical cation, complexes of pyridine with benzene and naphthalene radical cations, binary and ternary complexes of the hydroxyl radical with water (˙OH(H 2 O) and ˙OH(H 2 O) 2 ), and the pre-reactive complexes and transition states in the ˙OH + HCHO and ˙OH + CH 3 CHO reactions. These examples suggest that this second generation uALMO-EDA is a useful tool for furthering one's understanding of both energetic and property changes associated with radical–molecule interactions. 

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4. Variational Forward–Backward Charge Transfer Analysis Based on Absolutely Localized Molecular Orbitals: Energetics and Molecular Properties

   https://doi.org/10.1021/acs.jctc.9b01168  

   Loipersberger, Matthias; Mao, Yuezhi; Head-Gordon, Martin (January 2020, Journal of Chemical Theory and Computation)
5. Accurate and efficient DFT-based diabatization for hole and electron transfer using absolutely localized molecular orbitals

   https://doi.org/10.1063/1.5125275  

   Mao, Yuezhi; Montoya-Castillo, Andrés; Markland, Thomas E. (October 2019, The Journal of Chemical Physics)