Cancer Mutation Alters Mechanical Stiffness of Epithelial Cadherin Domains: A Molecular Dynamics Study

In different types of cancer, mutations in protein level lead to impaired structure and function. The epithelial cadherin plays a major role in the consistency of cell–cell adhesion and inhibits cancer progression. Reduced expression level of E-cadherin accompanied by the expression of mutated E-cadherin result in loss of cell adhesion and tendency to invade. To quantify the extent of effect of such mutations on mechanical properties of E-cadherin, we used steered molecular dynamics simulation. Since the mutations occur in different extracellular domains, each domain was modeled separately and two methods of simulations were implemented on the wild-type and mutated structures in gastric and prostate carcinomas. Another mutation was constructed to comply with original sequencing of the protein. Among different variables, number of hydrogen bonds and solvent accessible surface area were mostly influential. Alterations within the protein structure caused both stiffening and softening of the protein depending on the location of mutations and the nature of change in the protein structure. Substitution of a single amino acid induced by mutation considerably changed mechanical stiffness of a single domain. Deletion of four residues in a domain noticeably reduced the stiffness. Results may contribute to proper understanding of mechanisms involved in progression of cancer.