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Flavoproteins are a ubiquitous class of redox proteins, enzymes, and photoreceptors that derive their versatility from the flavin cofactor—a prosthetic group that serves as the main locus of their spectral, photophysical, and (photo)chemical properties. It is thus common for computational modeling of flavoproteins to employ a hybrid approach that treats the flavin quantum mechanically and the remaining atoms classically. Such quantum mechanical/molecular mechanical (QM/MM) methods have proven powerful for studying flavoproteins so far, but users are often faced with a choice between treating the flavin electronic structure with ab initio wave function methods or using more approximate methods that allow for more extensive sampling of the protein dynamics. Herein, we present APEC-F 2.0, an automated QM/MM workflow that uses several open-source software packages to construct QM/MM models of flavoproteins. Exploiting the rigidity of flavin’s tricyclic isoalloxazine ring, the APEC approach iteratively optimizes flavin’s geometry in a static MM environment that represents a dynamic protein using a superposition of configurations generated from molecular dynamics. The automation of the code enables the systematic construction of QM/MM models using a common protocol and is suitable for comparing flavin’s spectral, electronic, and chemical properties in different redox, protonation, or excited states in a wide range of flavoproteins. 

We report two novel pro-fluorescent, ethynylthiophene-basedo-nitrobenzyl photolabile protecting groups that absorb visible light and enable real-time visualization of hydroxamic acid release through a fluorescent nitrosoketone by-product. 

Abstract Upon blue‐light absorption, LOV domains efficiently undergo intersystem crossing (ISC) to the triplet state. Several factors potentially contribute to this efficiency. One often proposed in the literature is the heavy atom effect of the nearby (and eventually adduct‐forming) cysteine. However, some LOV domain derivatives that lack the cysteine residue also undergo ISC efficiently. Using hybrid multireference quantum mechanical/molecular mechanical (QM / MM) models, we investigated the effect of the electrostatic environment in a prototypal LOV domain,Arabidopsis thalianaPhototropin 1 LOV2 (AtLOV2), compared to the effect of the dielectric of an aqueous solution. We find that the electrostatic environment of AtLOV2 is especially well tuned to stabilize a triplet state, which we posit is the state involved in the ISC step. Other low‐lying triplet states that have and character are ruled out on the basis of energetics and/or their orbital character. The mechanistic picture that emerges from the calculations is one that involves the ISC of photoexcited flavin to a triplet state followed by rapid internal conversion to a triplet state, which is the state detected spectroscopically. This insight into the ISC mechanism can provide guidelines for tuning flavin's photophysics through mutations that alter the protein electrostatic environment and potentially helps to explain why ISC (and subsequent flavin photochemistry) does not occur readily in many classes of flavin‐binding enzymes. 

A rare cuprous triangle featuring a reactive organocopper site is captured by a new flexible bis(amidinate) ligand from the oligomeric mesitylcopper framework and interconverts with another equivalent of ligand into a tetracuprous Möbius strip. 

FTIR spectroscopy accompanied by quantum chemical simulations can reveal important information about molecular structure and intermolecular interactions in the condensed phase. Simulations typically account for the solvent either through cluster quantum mechanical (QM) models, polarizable continuum models (PCM), or hybrid quantum mechanical/molecular mechanical (QM/MM) models. Recently, we studied the effect of aqueous solvent interactions on the vibrational frequencies of lumiflavin, a minimal flavin model, using cluster QM and PCM models. Those models successfully reproduced the relative frequencies of four prominent stretching modes of flavin’s isoalloxazine ring in the diagnostic 1450–1750 cm−1 range but poorly reproduced the relative band intensities. Here, we extend our studies on this system and account for solvation through a series of increasingly sophisticated models. Only by combining elements of QM clusters, QM/MM, and PCM approaches do we obtain an improved agreement with the experiment. The study sheds light more generally on factors that can impact the computed frequencies and intensities of IR bands in solution.