DNA sequence-dependent ionic currents in ultra-small solid-state nanopores.
DNA sequence-dependent ionic currents in ultra-small solid-state nanopores.
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DOI：
10.1039/c6nr01061j
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发表时间：
2016-05-05
期刊：
影响因子：
6.7
通讯作者：
Aksimentiev A
中科院分区：
文献类型：
--
作者：
Comer J;Aksimentiev A
通过被DNA部分阻断的纳米孔的离子电流的测量已经成为表征DNA核苷酸序列的有力方法。虽然已经通过实验证明了核苷酸序列对纳米孔阻断电流的影响，但预测和解释这种测量仍然是一个巨大的挑战。使用原子分辨率计算方法，在这里，我们展示了序列，分子构象和孔几何形状如何影响模型固态纳米孔中的阻断离子电流。我们证明，从一个DNA分子的封锁电流是由至少三个连续的核苷酸的化学身份和构象。我们发现，尽管具有几乎相同的分子构象，但核苷酸三联体产生的阻断电流随其核苷酸序列而变化很大。令人鼓舞的是，我们发现在超小（1.6 nm × 1.1 nm横截面; 2 nm长度）固态纳米孔中，单碱基取代的阻断电流差异高达25%。尽管复杂的依赖性的封锁电流上的序列和构象的DNA三联体，我们发现，在许多条件下，胸腺嘧啶碱基的数量与电流呈正相关，而嘌呤碱基的数量和嘌呤和嘧啶的存在下，在三联体与电流呈负相关。基于这些观察，我们构建了一个简单的理论模型，该模型将离子电流与固态纳米孔的碱含量联系起来。此外，我们表明，紧凑的构象的DNA在狭窄的孔提供了最大的信号-噪声比为单碱基检测，而减少的纳米孔长度增加了离子电流噪声。因此，纳米孔阻断电流的序列依赖性可以在理论上合理化，尽管预测可能需要针对每种纳米孔类型进行定制。
Measurements of ionic currents through nanopores partially blocked by DNA have emerged as a powerful method for characterization of the DNA nucleotide sequence. Although the effect of the nucleotide sequence on the nanopore blockade current has been experimentally demonstrated, prediction and interpretation of such measurements remain a formidable challenge. Using atomic resolution computational approaches, here we show how the sequence, molecular conformation, and pore geometry affect the blockade ionic current in model solid-state nanopores. We demonstrate that the blockade current from a DNA molecule is determined by the chemical identities and conformations of at least three consecutive nucleotides. We find the blockade currents produced by the nucleotide triplets to vary considerably with their nucleotide sequence despite having nearly identical molecular conformations. Encouragingly, we find blockade current differences as large as 25% for single-base substitutions in ultra small (1.6 nm × 1.1 nm cross section; 2 nm length) solid-state nanopores. Despite the complex dependence of the blockade current on the sequence and conformation of the DNA triplets, we find that, under many conditions, the number of thymine bases is positively correlated with the current, whereas the number of purine bases and the presence of both purine and pyrimidines in the triplet are negatively correlated with the current. Based on these observations, we construct a simple theoretical model that relates the ion current to the base content of a solid-state nanopore. Furthermore, we show that compact conformations of DNA in narrow pores provide the greatest signal-to-noise ratio for single base detection, whereas reduction of the nanopore length increases the ionic current noise. Thus, the sequence dependence of nanopore blockade current can be theoretically rationalized, although the predictions will likely need to be customized for each nanopore type.