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Molecular dynamics, residue network analysis, and cross-correlation matrix to characterize the deleterious missense mutations in GALE causing galactosemia III

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Abstract

Epimerase-deficiency galactosemia (EDG) is caused by mutations in the UDP-galactose 4’-epimerase enzyme, encoded by gene GALE. Catalyzing the last reaction in the Leloir pathway, UDP-galactose-4-epimerase catalyzes the interconversion of UDP-galactose and UDP-glucose. This study aimed to use in-depth computational strategies to prioritize the pathogenic missense mutations in GALE protein and investigate the systemic behavior, conformational spaces, atomic motions, and cross-correlation matrix of the GALE protein. We searched four databases (dbSNP, ClinVar, UniProt, and HGMD) and major biological literature databases (PubMed, Science Direct, and Google Scholar), for missense mutations that are associated with EDG patients, our search yielded 190 missense mutations. We applied a systematic computational prediction pipeline, including pathogenicity, stability, biochemical, conservational, protein residue contacts, and structural analysis, to predict the pathogenicity of these mutations. We found three mutations (p.K161N, p.R239W, and p.G302D) with a severe phenotype in patients with EDG that correlated with our computational prediction analysis; thus, they were selected for further structural and simulation analyses to compute the flexibility and stability of the mutant GALE proteins. The three mutants were subjected to molecular dynamics simulation (MDS) with native protein for 200 ns using GROMACS. The MDS demonstrated that these mutations affected the beta-sheets and helical region that are responsible for the catalytic activity; subsequently, affects the stability and flexibility of the mutant proteins along with a decrease and more deviations in compactness when compared to that of a native. Also, three mutations created major variations in the combined atomic motions of the catalytic and C-terminal regions. The network analysis of the residues in the native and three mutant protein structures showed disturbed residue contacts occurred owing to the missense mutations. Our findings help to understand the structural behavior of a protein owing to mutation and are intended to serve as a platform for prioritizing mutations, which could be potential targets for drug discovery and development of targeted therapeutics.

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Acknowledgements

S.U.K. gratefully acknowledges the Indian Council of Medical Research (ICMR), India, for providing him with a Senior Research Fellowship [ISRM/11(93)/2019]. Also, we acknowledge V. Anu Preethi from VIT for her help in result analyses using R Studio. The authors thank the management of VIT for providing the facilities and the encouragement to carry out this work.

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Authors and Affiliations

  1. School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India

    S. Udhaya Kumar, Srivarshini Sankar, D. Thirumal Kumar, R. Siva & C. George Priya Doss

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

    Salma Younes, Nadin Younes & Hatem Zayed

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  1. S. Udhaya Kumar
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  2. Srivarshini Sankar
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  3. D. Thirumal Kumar
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  7. C. George Priya Doss
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Contributions

S.U.K., S.S., S.Y., N.Y., H.Z., and C.G.P.D. were involved in the design of the study and the acquisition, analysis, and interpretation of the data. S.U.K., D.T.K., C.G.P.D., and H.Z. were involved in the interpretation of the data and drafting the manuscript. G.P.D.C., R.S., and H.Z. supervised the entire study and were involved in study design, the acquisition, analysis, and interpretation of the data, and drafting the manuscript. The manuscript was reviewed and approved by all the authors.

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Correspondence to C. George Priya Doss or Hatem Zayed.

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Kumar, S.U., Sankar, S., Kumar, D.T. et al. Molecular dynamics, residue network analysis, and cross-correlation matrix to characterize the deleterious missense mutations in GALE causing galactosemia III. Cell Biochem Biophys 79, 201–219 (2021). https://doi.org/10.1007/s12013-020-00960-z

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