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Predicting enzyme-substrate specificity with QM/MM Methods: A case study of the stereo-specificity of D-glucarate dehydratase.

Tian B, Wallrapp FH, Kalyanaraman C, Zhao S, Eriksson LA, Jacobson MP (2013) Biochemistry 52, 5511-3. PMCID: PMC3964877

Computational prediction of enzyme function requires the ability to accurately score stereochemically distinct entities, a difficult but crucial challenge for EFI strategies to overcome. In this publication the Jacobson group uses a member of the Enolase Superfamily, D‑glucarate dehydratase, to test QM/MM methods. Such approaches will be essential for development of ways to predict chemical reactivity in addition to ligand specificity. For this enzyme, they observe that both the binding and chemical steps contribute to substrate specificity and that QM/MM calculations on the Michaelis complex may be a useful surrogate for such analyses instead of computationally intense transition states.  


The stereospecificity of d-glucarate dehydratase (GlucD) is explored by QM/MM calculations. Both the substrate binding and the chemical steps of GlucD contribute to substrate specificity. Although the identification of transition states remains computationally intensive, we suggest that QM/MM computations on ground states or intermediates can capture aspects of specificity that cannot be obtained using docking or molecular mechanics methods.

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Table of Contents 

Scheme 1. Catalytic Mechanism of GlucD and the Structures of the Three Nonsubstrates

Scheme 2. QM Region in the QM/MM Calculations

Figure 1. Energy profiles (in kcal/mol) along the reaction coordinate for d-glucarate (in black), m-allarate (in red), d-mannarate (in green), and d-altrarate (in blue).

Reprinted with permission from Biochemistry. Copyright 2013 American Chemical Society.