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Computational approach to unravel the impact of missense mutations of proteins (D2HGDH and IDH2) causing D-2-hydroxyglutaric aciduria 2

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Abstract

The 2-hydroxyglutaric aciduria (2-HGA) is a rare neurometabolic disorder that leads to the development of brain damage. It is classified into three categories: D-2-HGA, L-2-HGA, and combined D,L-2-HGA. The D-2-HGA includes two subtypes: type I and type II caused by the mutations in D2HGDH and IDH2 proteins, respectively. In this study, we studied six mutations, four in the D2HGDH (I147S, D375Y, N439D, and V444A) and two in the IDH2 proteins (R140G, R140Q). We performed in silico analysis to investigate the pathogenicity and stability changes of the mutant proteins using pathogenicity (PANTHER, PhD-SNP, SIFT, SNAP, and META-SNP) and stability (i-Mutant, MUpro, and iStable) predictors. All the mutations of both D2HGDH and IDH2 proteins were predicted as disease causing except V444A, which was predicted as neutral by SIFT. All the mutants were also predicted to be destabilizing the protein except the mutants D375Y and N439D. DSSP plugin of the PyMOL and Molecular Dynamics Simulations (MDS) were used to study the structural changes in the mutant proteins. In the case of D2HGDH protein, the mutations I147S and V444A that are positioned in the beta sheet region exhibited higher Root Mean Square Deviation (RMSD), decrease in compactness and number of intramolecular hydrogen bonds compared to the mutations N439D and D375Y that are positioned in the turn and loop region, respectively. While the mutants R140Q and R140QG that are positioned in the alpha helix region of the protein. MDS results revealed the mutation R140Q to be more destabilizing (higher RMSD values, decrease in compactness and number of intramolecular hydrogen bonds) compared to the mutation R140G of the IDH2 protein. This study is expected to serve as a platform for drug development against 2-HGA and pave the way for more accurate variant assessment and classification for patients with genetic diseases.

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Abbreviations

D-2-HGA:

D-2-hydroxyglutaric aciduria

L-2-HGA:

L-2-hydroxyglutaric aciduria

D, L-2-HGA:

Combined D, L-2-hydroxyglutaric aciduria

D2HGDH:

D-2-Hydroxyglutarate Dehydrogenase

IDH2:

Isocitrate dehydrogenase

ddG:

stability free energy change

RMSD:

Root Mean Square Deviation

Rg:

Radius of Gyration

DSSP:

Database of secondary structure assignments (and much more) for all protein entries in the Protein Data Bank

MDS:

Molecular Dynamics Simulation

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Acknowledgements

The authors acknowledge the management of Vellore Institute of Technology, Vellore, India and (BRAF) @ CDAC for providing the facilities required to perform this work.

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  1. Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India

    D. Thirumal Kumar, L. Jerushah Emerald, C. George Priya Doss, P. Sneha & R. Siva

  2. Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, 600116, India

    W. Charles Emmanuel Jebaraj

  3. Department of Biomedical Sciences, College of Health and Sciences, Qatar University, Doha, Qatar

    Hatem Zayed

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  1. D. Thirumal Kumar
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Thirumal Kumar, D., Jerushah Emerald, L., George Priya Doss, C. et al. Computational approach to unravel the impact of missense mutations of proteins (D2HGDH and IDH2) causing D-2-hydroxyglutaric aciduria 2. Metab Brain Dis 33, 1699–1710 (2018). https://doi.org/10.1007/s11011-018-0278-3

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