Modelling cadherin-mediated protein-protein interactions by atomistic simulations

Cadherins are cell-cell adhesion proteins which are overexpressed in several solid tumors. They contain an extracellular region consisting of five immunoglobulin-like domains that extend from the cell surface. In 1995, structural data of the N-cadherin suggested an homodimeric interface involving the peptide chains HAVDI and INPI contained in the extracellular domain. Based on these studies, mimics of His-Ala-Val sequence have been patented. More recently, the crystal structures of the complete ectodomains of N- and E-cadherins have been solved highlighting that cadherins dimerize through a ‘strand-swap’ trans-adhesive interface involving the N-terminal EC1 domains. In this framework, a thorough study of the adhesion dimer structures was attempted with the aim of characterizing cadherin binding interfaces and developing computational tools for the design of small peptidomimetics that target the homophilic interactions of the extracellular cadherin domains. The communication will discuss in particular the metadynamics simulations performed on E-cadherin in order to observe the first step of the 'strand-swap' mechanism, the conformational change resulting in the opening of adhesion arm. Using an enhanced sampling approach is the only way to reconstruct the lowest free-energy path that connects an initial state to a final one in case of events that occur in the micro-millisecond time scale. A complete understanding of the cadherin-mediated cell-cell adhesion is fundamental in view of developing small molecules targeting the homophilic interaction of overly expressed cadherins in tumour cells. The computer-aided design of small peptidomimetics found by virtual screening of database and rational design of tetrapeptide mimics has already been started and a few candidates have already been synthesized and tested.