Deciphering the impact of missense mutations on structure and dynamics of SMAD4 protein involved in pathogenesis of gall bladder cancer

Abstract

Gall bladder cancer (GBC) is the most common malignancy of biliary tract cancer associated with high mortality rate and poor prognosis due to lack of suitable biomarkers. In this study, we explored the structural and functional effects of different missense mutations occurs in SMAD4 that was associated with the development of GBC. We utilized in silico methods to predict the harmful effects of nonsynonymous missense mutations and monitored the stability of protein. We found that all mutations (D351N, G352E, R361C, R361H, E526Q) associated with SMAD4 were deleterious in nature resulting in the formation of deformed or unstable protein structure. Molecular dynamics simulation studies revealed how these mutations affect protein stability, structure, conformation and function. We observed, different mutants increase the compactness and rigidity of SMAD4 protein, alter secondary structure composition, decrease the surface area and protein-ligand interaction and affect its conformation. Findings of current work indicated that the analyzed mutations might affect the structure of protein and its caliber to interact with other molecules, which probably related to functional impairment of SMAD4 upon D351N, G352E, R361C, R361H, E526Q mutations and their involvement in cancer. Hence, the present study has significance of rational drug design and further increase our understanding of GBC development.

Communicated by Ramaswamy H. Sarma

Keywords:

• Gall bladder cancer
• missense mutations
• wildtype
• mutant
• MD simulation
• essential dynamics

Acknowledgements

We thank Neetu and Supriya for providing the SNVs information. Author thanks anonymous reviewers for their valuable comments and suggestions.

Disclosure statement

No potential conflict of interest is reported by the author(s).

Author contributions

R.K. conceptualized, designed and performed the experiments. R.K help in performing the bioinformatics work. R.K., S.K., N.R.D., P.D. and S.H. help in literature study. R.K. analysed the data and wrote the manuscript. R.K. and P.T. help in writing the manuscript. P.T. and G.K.R. provided the laboratory infrastructure. R.K., R.K. and P.T. read and approved the final version of manuscript.

Additional information

Funding

Indian Council of Medical Research, Grant/Award Number: 5/13/1/TF/2015/NCD-III.