Abstract
Studying the conformations involved in the dimerization of cadherins is highly relevant to understand the development of tissues and its failure, which is associated with tumors and metastases. Experimental techniques, like X-ray crystallography, can usually report only the most stable conformations, missing minority states that could nonetheless be important for the recognition mechanism. Computer simulations could be a valid complement to the experimental approach. However, standard all-atom protein models in explicit solvent are computationally too demanding to search thoroughly the conformational space of multiple chains composed of several hundreds of amino acids. To reach this goal, we resorted to a coarse-grained model in implicit solvent. The standard problem with this kind of model is to find a realistic potential to describe its interactions. We used coevolutionary information from cadherin alignments, corrected by a statistical potential, to build an interaction potential, which is agnostic about the experimental conformations of the protein. Using this model, we explored the conformational space of multichain systems and validated the results comparing with experimental data. We identified dimeric conformations that are sequence specific and that can be useful to rationalize the mechanism of recognition between cadherins.
Highlights
Cadherins are surface proteins responsible for cell−cell recognition and adhesion.[1]
We simulated the dynamics of EC1 of N, E, and P-cadherins in conditions of infinite dilution where the protein is monomeric
Using a united-atom representation in which each amino acid is represented by 4 atoms and the solvent is treated implicitly, we could sample at equilibrium the conformational space of two copies of the EC1-2 domains with advanced Monte Carlo algorithms in a few days of the computational time
Summary
Cadherins are surface proteins responsible for cell−cell recognition and adhesion.[1] They are involved in different stages of tumor progression, like in angiogenesis[2] and metastasis,[3] and several germline mutations are found in solid tumors.[4] For this reason, they are important potential targets of antitumoral molecules. A large number of members of the cadherin superfamily have been discovered. Important for their relationship with cancer are the so-called “classical” cadherins of types I and II, which are present only in vertebrates and classified according to the tissue where they were first identified. The human genome encodes 114 cadherins for example E-cadherin was found in epithelial tissues, N-cadherin in neurons, and Pcadherin in placenta.[5]
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