title: Trans-cis switching mechanisms in proline analogues and their relevance for the gating of the 5-HT3 receptor.
abstract: Trans-cis isomerization of a proline peptide bond is a potential mechanism to open the channel of the 5-HT(3) receptor. Here, we have used the metadynamics method to theoretically explore such a mechanism. We have determined the free energy surfaces in aqueous solution of a series of dipeptides of proline analogues and evaluated the free energy difference between the cis and trans isomers. These theoretical results were then compared with data from mutagenesis experiments, in which the response of the 5-HT(3) receptor was measured when the proline at the apex of the M2-M3 transmembrane domain loop was mutated. The strong correlation between the experimental and the theoretical data supports the existence of a trans-cis proline switch for opening the 5-HT(3) receptor ion channel.
authors: Physics Department, King's College London, Strand, London, WC2R 2LS U.K.
authors: Claudio
authors: C
authors: Melis
authors: Giovanni
authors: G
authors: Bussi
authors: Sarah C R
authors: SC
authors: Lummis
authors: Carla
authors: C
authors: Molteni
mesh_terms: D000465:Algorithms; D001703:Biophysics / Q000379:methods*; D003198:Computer Simulation; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D016296:Mutagenesis; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D011392:Proline / Q000737:chemistry*; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry*; D012984:Software; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D010455:Peptides; D044406:Receptors, Serotonin, 5-HT3; D014867:Water; D011392:Proline