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Conformational Behavior of Flavin Adenine Dinucleotide: Conserved Stereochemistry in Bound and Free States

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Center for Informational Biology, Ochanomizu University, 2-1-1 Otsuka, Bunkyo, Tokyo 112-8610, Japan
Graduate School of Humanities and Sciences, Ochanomizu University, 2-1-1 Otsuka, Bunkyo, Tokyo 112-8610, Japan
§ National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan
Institute for Life Science and Technology, Hanzehogeschool Groningen, 9747 AS/9700 RM Groningen, The Netherlands
*E-mail: [email protected]. Phone/Fax: +81-3-5978-5514.
Cite this: J. Phys. Chem. B 2014, 118, 47, 13486–13497
Publication Date (Web):November 12, 2014
Copyright © 2014 American Chemical Society

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    Metabolic enzymes utilize the cofactor flavin adenine dinucleotide (FAD) to catalyze essential biochemical reactions. Because these enzymes have been implicated in disease pathways, it will be necessary to target them via FAD-based structural analogues that can either activate/inhibit the enzymatic activity. To achieve this, it is important to explore the conformational space of FAD in the enzyme-bound and free states. Herein, we analyze X-ray crystallographic data of the enzyme-bound FAD conformations and sample conformations of the molecule in explicit water by molecular dynamics (MD) simulations. Enzyme-bound FAD conformations segregate into five distinct groups based on dihedral angle principal component analysis (PCA). A notable feature in the bound FADs is that the adenine base and isoalloxazine ring are oppositely oriented relative to the pyrophosphate axis characterized by near trans hypothetical dihedral angle “δV” values. Not surprisingly, MD simulations in water show final compact but not perfectly stacked ring structures in FAD. Simulation data did not reveal noticeable changes in overall conformational dynamics of the dinucleotide in reduced and oxidized forms and in the presence and/or absence of ions. During unfolding–folding dynamics, the riboflavin moiety is more flexible than the adenosine monophosphate group in the molecule. Conversely, the isoalloxazine ring is more stable than the variable adenine base. The pyrophosphate group depicts an unusually highly organized fluctuation illustrated by its dihedral angle distribution. Conformations sampled from enzymes and MD are quantified. The extent to which the protein shifts the distribution from the unbound state is discussed in terms of prevalent FAD shapes and dihedral angle population.

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    Dihedral angle definitions, free energy landscape plots, select dihedral angle scatter maps and their trajectories, and SASA of FADH2–water interactions. This material is available free of charge via the Internet at

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