Forced Dissociation of the Strand Dimer Interface between C-Cadherin Ectodomains

Theforce-induceddissociationofthestrand dimer interface in C-cadherin has been studied using steered molecular dynamics simulations. The dissocia- tion occurred, without domain unraveling, after the ex- traction of the conserved trypthophans (Trp2) from their respective hydrophobic pockets. The simulations re- vealed two stable positions for the Trp2 side chain in- side the pocket. The most internal stable position in- volved a hydrogenbond between thering Ne of Trp2 and the backbone carbonyl of Glu90. In the second stable position, the aromatic ring is located at the pocket en- trance. After extracting the two tryptophans from their pockets, the complex exists in an intermediate bound statethatinvolvesaclosepackingofthetryptophanswith residues Asp1 and Asp27 from both domains. Dissocia- tion occurred after this residue association was broken. Simulations carried out with a complex formed between W2A mutants showed that the mutant complex dissoci- ates more easily than the wild type complex does. These results correlate closely with the role of the conserved tryptophans suggested previously by site directed muta- genesis.