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

Publication date: Available online 26 May 2016 Source:Journal of Molecular Graphics and Modelling Author(s): Warot Chotpatiwetchkul, Nathjanan Jongkon, Supa Hannongbua, M. Paul Gleeson 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 k cat 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. Graphical abstract
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research