Trans-cis isomerization of a proline peptide bond is a potential mechanism to open the channel of the 5-HT3 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-HT3 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-HT3 receptor ion channel.
|Titolo:||Trans-cis switching mechanisms in proline analogues and their relevance for the gating of the 5-HT3 receptor|
|Autori:||Melis C; Bussi G; Lummis SCR; Molteni C|
|Rivista:||JOURNAL OF PHYSICAL CHEMISTRY. B, CONDENSED MATTER, MATERIALS, SURFACES, INTERFACES & BIOPHYSICAL|
|Data di pubblicazione:||2009|
|Digital Object Identifier (DOI):||10.1021/jp9046962|
|Appare nelle tipologie:||1.1 Journal article|