Many ion channels are known to behave as an allosteric protein, coupling environmental stimuli captured by specialized sensing domains to the opening of a central pore. The classic Monod-Wyman-Changeux (MWC) model, originally proposed to describe binding of gas molecules to hemoglobin, has been widely used as a framework for analyzing ion channel gating. Here, we address the issue of how accurately the MWC model predicts activation of the capsaicin receptor TRPV1 by vanilloids. Taking advantage of a concatemeric design that makes it possible to lock TRPV1 in states with zero to four bound vanilloid molecules, we showed quantitatively that the overall gating behavior is satisfactorily predicted by the MWC model. There is, however, a small yet detectable subunit position effect: ligand binding to two kitty-corner subunits is 0.3–0.4 kcal/mol more effective in inducing opening than binding to two neighbor subunits. This difference—less than 10% of the overall energetic contribution from ligand binding—might be due to the restriction on subunit arrangement imposed by the planar membrane; if this is the case, then the position effect is not expected in hemoglobin, in which each subunit is related equivalently to all the other subunits.

中文翻译：

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TRPV1 与理想的 MWC 型蛋白的偏差有多少？

已知许多离子通道表现为变构蛋白，将专门的传感域捕获的环境刺激与中心孔的开口耦合。经典的 Monod-Wyman-Changeux (MWC) 模型最初是为了描述气体分子与血红蛋白的结合而提出的，现已广泛用作分析离子通道门控的框架。在这里，我们解决了 MWC 模型如何准确地预测香草类化合物激活辣椒素受体 TRPV1 的问题。利用串联设计，可以将 TRPV1 锁定在具有 0 到 4 个结合香草醛分子的状态，我们定量地表明，MWC 模型可以令人满意地预测总体门控行为。然而，存在一个小但可检测的亚基位置效应：配体与两个小猫角亚基的结合在诱导开放方面比与两个相邻亚基的结合更有效 0.3-0.4 kcal/mol。这种差异（不到配体结合的总能量贡献的 10%）可能是由于平面膜对亚基排列的限制所致；如果是这种情况，则血红蛋白中不会出现位置效应，其中每个亚基与所有其他亚基等效相关。