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.