Insights into the Mechanisms of K+ Permeation in K+ Channels from Computer Simulations.,Journal of Chemical Theory and Computation

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Insights into the Mechanisms of K+ Permeation in K+ Channels from Computer Simulations.
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2019-12-20 , DOI: 10.1021/acs.jctc.9b00971
Victoria Oakes ₁ , Simone Furini ₂ , Carmen Domene _{1,

3}

Affiliation

Ion permeation, selectivity, and the behavior of the K+ channel selectivity filter have been studied intensively in the previous two decades. The agreement among multiple approaches used to study ion flux in K+ channels suggests a consensus mechanism of ion permeation across the selectivity that has been put to the test in recent years with the proposal of an alternative way by which ions can cross the selectivity filter of K+ channels via direct Coulomb repulsion between contacting cations. Past experimental work by Zhou and MacKinnon (J. Mol. Biol. 2004, 338, 839) showed that mutation of the site S4 reduces the total occupancy of the selectivity filter to less than two ions on average by lowering the occupancy of the S2-S4 configuration without changing the S1-S3 configuration much, and this reduction of occupancy means that ion configurations different from the ones involved in the canonical mechanism are likely to be involved. At that time, calculations using complicated kinetic networks to relate occupancy to conduction did not provide deeper insight into the conduction mechanism. Here, to help solve this enigma, umbrella sampling simulations have been performed to evaluate the potential of mean force of two KcsA mutant channels where the S4 site is substituted. Our new results provide insights into the significance of threonine in this position, revealing the effect of substitution on the alternate mechanisms of conduction proposed, involving either water or vacant sites.

中文翻译：

通过计算机模拟洞悉K +通道中K +渗透的机理。

在过去的二十年中，对离子渗透，选择性和K +通道选择性过滤器的行为进行了深入研究。用于研究K +通道中离子通量的多种方法之间的共识表明，跨选择性的离子渗透的共识机制已在近年来进行了测试，并提出了一种离子可以穿过K +选择性过滤器的替代方法的建议。通过直接接触阳离子之间的库仑排斥作用的通道。Zhou和MacKinnon（J. Mol。Biol。2004，338，839）过去的实验工作表明，位点S4的突变通过降低S2-的占有率，将选择性过滤器的总占有率降低到平均少于两个离子。 S4配置，无需过多更改S1-S3配置，占用率的降低意味着可能会涉及与规范机制所涉及的离子配置不同的离子配置。当时，使用复杂的动力学网络将占有率与传导相关联的计算并未提供对传导机制的更深入了解。在这里，为了帮助解决这个难题，已经进行了总括抽样模拟，以评估替换了S4位点的两个KcsA突变体通道的平均力的潜力。我们的新结果提供了关于苏氨酸在该位置的重要性的见解，揭示了取代对拟议的其他传导机制的影响，涉及水或空位。使用复杂的动力学网络将占有率与传导相关联的计算并没有提供对传导机制的更深入的了解。在这里，为了帮助解决这个难题，已经进行了总括抽样模拟，以评估替换了S4位点的两个KcsA突变体通道的平均力的潜力。我们的新结果提供了关于苏氨酸在该位置的重要性的见解，揭示了取代对拟议的其他传导机制的影响，涉及水或空位。使用复杂的动力学网络将占有率与传导相关联的计算并没有提供对传导机制的更深入的了解。在这里，为了帮助解决这个难题，已经进行了总括抽样模拟，以评估替换了S4位点的两个KcsA突变体通道的平均力的潜力。我们的新结果提供了关于苏氨酸在该位置的重要性的见解，揭示了取代对拟议的其他传导机制的影响，涉及水或空位。

更新日期：2019-12-20

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