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

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• 作者：Claudio Melis ; Giovanni Bussi ; Sarah C. R. Lummis ; Carla Molteni
• 刊名：Journal of Physical Chemistry B
• 出版年：2009
• 出版时间：September 3, 2009
• 年：2009
• 卷：113
• 期：35
• 页码：12148-12153
• 全文大小：354K
• 年卷期：v.113,no.35(September 3, 2009)
• ISSN：1520-5207

文摘

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.