Computational studies of membrane transport proteins

次级活性转运蛋白是一类膜蛋白，其使用预先存在的分子浓度梯度作为能量来源，用于逆其浓度梯度转运另一种底物，例如营养物或神经递质。这个过程需要蛋白质改变构象，以便在称为交替进入的循环中暴露到膜一侧或另一侧上的底物结合位点的通路。每种生物都表达几十种不同的二级转运蛋白，这些蛋白表现出一套不同的结构，尽管总是具有某种形式的内部结构对称性。在过去的十年中，从三维结构中获得了前所未有的突破性见解。然而，详细了解每种膜转运蛋白的机制，以及它如何受其环境中的因素调节，需要了解其在更多构象状态下的结构，包括鉴定底物的结合区域。此外，蛋白质两端的高动态片段通常负责调节作用，需要额外的努力来表征。在过去的一年里，我们小组正在进行的研究继续调查几种不同的膜蛋白，包括血清素转运体SERT，甜菜碱同向转运体BetP和线粒体丙酮酸载体MPC，使用先进的结构预测技术和分子动力学模拟这些问题。这些工作正在与实验室合作进行，以促进对膜运输和调节机制的理解。

Secondary active transporters are a class of membrane proteins that use pre-existing molecular concentration gradients as an energy source for translocating another substrate, such as a nutrient or a neurotransmitter, against its concentration gradient. This process requires the protein to change conformations so as to expose a pathway to the substrate binding site(s) on one or other side of the membrane, in a cycle known as alternating access. Every organism expresses dozens of different secondary transporter proteins, and these exhibit a diverse set of architectures, albeit always with some form of internal structural symmetry. Unprecedented, ground-breaking insights have been garnered from three-dimensional structures obtained in the last decade. Nevertheless, a detailed understanding of the mechanism of each membrane transport protein, and how it is regulated by factors in its environment, requires knowledge of its structure in many more conformational states, including identification of the binding regions for the substrate or substrates. In addition, highly-dynamic segments at either end of the protein, which are often responsible for regulatory roles, require additional effort to characterize. Ongoing studies from our group over the last year have continued to investigate these questions for several different membrane proteins, including serotonin transporter SERT, the betaine symporter BetP, and mitochondrial pyruvate carrier MPC, using advanced structure prediction techniques and molecular dynamics simulations. These efforts are being carried out in collaboration with experimental laboratories, to drive understanding of the mechanism of membrane transport and regulation.