a fully atomistic model of the cx32 connexon一个完全的原子论的模型cx32接合质.pdfVIP

A Fully Atomistic Model of the Cx32 Connexon Sergio Pantano1,2,3*, Francesco Zonta2,3, Fabio Mammano2,3,4* 1 Institut Pasteur of Montevideo, Montevideo, Uruguay, 2 Venetian Institute of Molecular Medicine (VIMM), Padova, Italy, 3 Consorzio Nazionale Interuniversitario per le ` Scienze Fisiche della Materia (CNISM), Rome, Italy, 4 Dipartimento di Fisica ‘‘G.Galilei’’, Universita di Padova, Padova, Italy Abstract Connexins are plasma membrane proteins that associate in hexameric complexes to form channels named connexons. Two connexons in neighboring cells may dock to form a ‘‘gap junction’’ channel, i.e. an intercellular conduit that permits the direct exchange of solutes between the cytoplasm of adjacent cells and thus mediate cell–cell ion and metabolic signaling. The lack of high resolution data for connexon structures has hampered so far the study of the structure–function relationships that link molecular effects of disease–causing mutations with their observed phenotypes. Here we present a combination of modeling techniques and molecular dynamics (MD) to infer side chain positions starting from low resolution structures containing only Ca atoms. We validated this procedure on the structure of the KcsA potassium channel, which is solved at atomic resolution. We then produced a fully atomistic model of a homotypic Cx32 connexon starting from a published model of the Ca carbons arrangement for the connexin transmembrane helices, to which we added extracellular and cytoplasmic loops. To achieve structural relaxation within a realistic environment, we used MD simulations inserted in an explicit solvent–membrane context and we subsequently check