ERA-Chemistry: Design and synthesis of biologically inspired ion-conducting nanopores

人造纳米孔是高通量DNA测序仪等新兴纳米设备的关键部件。它们在浓度和电压梯度下工作，但对这些条件下的选择性和精馏等一般性问题知之甚少。模拟这些非平衡条件的计算手段仍然有限。在这里，我们将在与实验相同的条件下对钠离子通道激发的纳米孔进行新颖的稳态非平衡模拟(包括朗之万动力学、动态蒙特卡罗和局部平衡蒙特卡罗等多种技术)。这些条件包括固定电压的电极和固定电解液浓度的浴液。这些边界条件为稳态输运提供了驱动力。首先，我们将重点关注开放状态下的细菌NavMS通道，对于该通道，我们可以获得实验结构信息。对野生型蛋白质和突变体的模拟将得到全原子分子动力学计算的补充。模拟的结果将与我们的合作者C.Fahlke教授(德国Forschungszentum Jülich)进行的实验进行验证。这一建议扩展了我们和其他人之前开发的工具包，以构建通道和膜的粗粒度(CG)模型。将设计和模拟野生型和突变型NavMS通道的CG模型。最有希望的突变体将被用来提出人工纳米孔设计，这些突变体在钾对钠的选择性(以及单价对二价的选择性)和电压响应方面具有很好的选择性。电压响应包括通过施加在第三个电极上的电压对两个电极之间的电流进行整流和控制。纳米孔的设计将通过CG模型的模拟进行测试，并将由我们的实验合作者Z.Siwy(美国加州大学欧文分校)建造和测试。

Artificial nanopores are crucial components for emerging nanodevices such as high-throughput DNA sequencers. They function under concentration and voltage gradients, but generic issues such as selectivity and rectification under these conditions are poorly understood. Computational means to simulate these non-equilibrium conditions are still limited. Here we will carry out novel steady-state non-equilibrium simulations (including diverse techniques such as Langevin Dynamics, Dynamic Monte Carlo, and Local Equilibrium Monte Carlo) of Na+ channel-inspired nanopores under the same conditions as experiment. These conditions include electrodes at fixed voltages and baths of fixed electrolyte concentrations. These boundary conditions provide the driving force for the steady state transport. First, we will focus on the bacterial NavMs channel in the open state, for which experimental structural information is available. Simulations of the wild-type protein and of mutants will be complemented by all-atom Molecular Dynamics calculations. The findings of the simulations will be tested against experiments performed by our collaborator Prof. C. Fahlke (Forschungszentrum Jülich, Germany). This proposal extends a toolkit previously developed by us and others to construct coarse-grained (CG) models of channels and membranes. A CG model of the wild-type and mutant NavMs channel will be designed and simulated.The most promising mutants in terms of selectivity of potassium against sodium (and also of monovalent against divalent) and voltage response will be used to propose artificial nanopore designs. Voltage response includes rectification and control of current between two electrodes by the voltage applied at a third electrode. Nanopores designs will be tested by simulations of CG models and will be constructed and tested by our experimental collaborator Z. Siwy (U. of California at Irvine, US).