QM/MM investigation of the reaction rates of substrates of 2,3-dimethylmalate lyase: A catabolic protein isolated from Aspergillus niger

•QM/MM has been used to assess the catalytic activity of dimethylmalate lyase (DMML).•We investigate the reactivity of 5 substrates with differing reactivity at DMML.•The predicted barriers to reaction for the substrates show good agreement with the experimental kcat values.•The observation that suggest that the method may be of sufficient utility for design purposes.

Aspergillus niger is an industrially important microorganism used in the production of citric acid. It is a common cause of food spoilage and represents a health issue for patients with compromised immune systems. Recent studies on Aspergillus niger have revealed details on the isocitrate lyase (ICL) superfamily and its role in catabolism, including (2R, 3S)-dimethylmalate lyase (DMML). Members of this and related lyase super families are of considerable interest as potential treatments for bacterial and fungal infections, including Tuberculosis. In our efforts to better understand this class of protein, we investigate the catalytic mechanism of DMML, studying five different substrates and two different active site metals configurations using molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. We show that the predicted barriers to reaction for the substrates show good agreement with the experimental kcat values. This results help to confirm the validity of the proposed mechanism and open up the possibility of developing novel mechanism based inhibitors specifically for this target.

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