An automated QM/MM average protein electrostatic configuration approach for flavoproteins: APEC-F 2.0

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.