Selectivity in K+ channels is due to topological control of the permeant ion's coordinated state
Selectivity in K+ channels is due to topological control of the permeant ion's coordinated state
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DOI：
10.1073/pnas.0700554104
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发表时间：
2007-05-29
影响因子：
11.1
通讯作者：
Brooks, Charles L., III
中科院分区：
文献类型：
--
作者：
Bostick, David L.;Brooks, Charles L., III
K+通道的选择性过滤器提供偶极羰基配体、水和渗透阳离子之间的特定配位相互作用，这允许K+相对于（最重要的是）Na+选择性地流过细胞膜。虽然结构的观点属性K+的选择性提供的过滤器的配位几何形状，最近的分子动力学模拟研究将其归因于动态和独特的化学/静电性能的过滤器的羰基配体。在这里，我们提供了一个简单的理论分析K+和Na+络合与水的背景下，简化的结合位点模型和散装溶液。我们的分析表明，水分子和羰基基团都可以提供K+的选择性环境，如果对配合物的配位数施加等效的限制。缺乏这样的约束会消除选择性，表明无论配位配体是水分子还是羰基，“外部”或“拓扑”约束/力必须施加在离子配位复合物上以引发选择性结合。这些力必然来自通道蛋白，因为在本体水中，根据定义，呈现非选择性介质，配位数被允许放松以适应离子。我们发现，K+通道结合位点的配位几何形状是复制的8倍络合的K+在水和简化的结合位点模型，由于在一个复杂的局部相互作用的主导地位，因此是拓扑约束的配位数到一个特定的值的要求。
The selectivity filter of K+ channels provides specific coordinative interactions between dipolar carbonyl ligands, water, and the permeant cation, which allow for selective flow of K+ over (most importantly) Na+ across the cell membrane. Although a structural viewpoint attributes K+ selectivity to coordination geometry provided by the filter, recent molecular dynamics simulation studies attribute it to dynamic and unique chemical/electrostatic properties of the filter's carbonyl ligands. Here we provide a simple theoretical analysis of K+ and Na+ complexation with water in the context of simplified binding site models and bulk solution. Our analysis reveals that water molecules and carbonyl groups can both provide K+ selective environments if equivalent constraints are imposed on the coordination number of the complex. Absence of such constraints annihilates selectivity, demonstrating that whether a coordinating ligand is a water molecule or a carbonyl group, "external" or "topological" constraints/forces must be imposed on an ion-coordinated complex to elicit selective binding. These forces must inevitably originate from the channel protein, because in bulk water, which, by definition, presents a nonselective medium, the coordination number is allowed to relax to suit the ion. We show that the coordination geometry of K+ channel binding sites is replicated by 8-fold complexation of K+ in both water and simplified binding site models due to dominance of local interactions within a complex and is thus a requirement for topologically constraining the coordination number to a specific value.