Journal
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
Volume 68, Issue -, Pages 29-38Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2016.05.010
Keywords
DMML; QM/MM; Molecular dynamics (MD); Aspergillus niger
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Funding
- Kasetsart University Research and Development Institute (KURDI)
- Faculty of Science at Kasetsart University
- Thailand Research Fund (TRF) [RSA5480016]
- Department of Chemistry, Faculty of Science, Kasetsart University
- National Research University (NRU)
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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. (C) 2016 Elsevier Inc. All rights reserved.
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