Trans−cis Switching Mechanisms in Proline Analogues and Their Relevance for the Gating of the 5-HT3 Receptor | Zendy

Claudio Melis | Zendy; Giovanni Bussi | Zendy; Sarah C. R. Lummis | Zendy; Carla Molteni | Zendy

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Trans−cis Switching Mechanisms in Proline Analogues and Their Relevance for the Gating of the 5-HT₃ Receptor

Author(s) -

Claudio Melis,

Giovanni Bussi,

Sarah C. R. Lummis,

Carla Molteni

Publication year - 2009

Publication title -

the journal of physical chemistry b

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 0.864

H-Index - 392

eISSN - 1520-6106

pISSN - 1520-5207

DOI - 10.1021/jp9046962

Subject(s) - proline , chemistry , metadynamics , gating , isomerization , mutagenesis , stereochemistry , receptor , cis–trans isomerism , transmembrane domain , biophysics , molecular dynamics , biochemistry , amino acid , mutant , computational chemistry , biology , gene , catalysis

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.

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