Reconstructing the free energy landscape of E-Cadherin conformational transition by metadynamics simulations

In classical cadherins, the mechanism by which three dimensional (3D) domain swapping leads to protein dimerization is still debated[1]. According to the 3D swapping model, two cadherin monomers mutually exchange a small portion of their N-terminal extracellular domain and form a homodimer. Two possible dimerization pathways have been proposed: a selected fit mechanism, based on the hypothesis that only monomers in an active conformational state can bind, and the induced fit mechanism, which requires the formation of an intermediate complex preceding the dimerization. Exploiting the advantages of metadynamics simulations in sampling protein conformational changes, the selected fit mechanism has been tested by reconstructing the free energy profile of E-cadherin monomer conformational change, leading to the active form. Calculations have also showed that the E-cadherin free state conformational equilibrium is strongly affected by the presence of calcium ions, which behave as allosteric activators in the opening process. We acknowledge HPC-Europa2 Programme (Application number 1024) and the Ministero dell'Università e della Ricerca (bando FIRB 2008 RBFR088ITV) for financial support.