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Revisiting the Origin of Nanopore Current Blockage for Volume Difference Sensing at the Atomic Level.

ABSTRACT: Changes in the nanopore ionic current during entry of a target molecule underlie the sensing capability and dominate the intensity and extent of applications of the nanopore approach. The volume exclusion model has been proposed and corrected to describe the nanopore current blockage. However, increasing evidence shows nonconformity with this model, suggesting that the ionic current within a nanopore should be entirely reconsidered. Here, we revisit the origin of nanopore current blockage from a theoretical perspective and propose that the noncovalent interactions between a nanopore and a target molecule affect the conductance of the solution inside the nanopore, leading to enhanced current blockage. Moreover, by considering the example of an aerolysin nanopore discriminating the cytosine DNA and methylcytosine DNA that differ by a single methyl group, we completely demonstrate, by nanopore experiments and molecular dynamics simulations, the essential nature of this noncovalent interaction for discrimination. Our conductance model suggests multiplicative effects of both volume exclusion and noncovalent interaction on the current blockage and provides a new strategy to achieve volume difference sensing at the atomic level with highly specific current events, which would promote the nanopore protein sequencing and its applications in real-life systems.

SUBMITTER: Li MY

PROVIDER: S-EPMC8395674 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Revisiting the Origin of Nanopore Current Blockage for Volume Difference Sensing at the Atomic Level.

Li Meng-Yin MY Ying Yi-Lun YL Yu Jie J Liu Shao-Chuang SC Wang Ya-Qian YQ Li Shuang S Long Yi-Tao YT

JACS Au 20210527 7

Changes in the nanopore ionic current during entry of a target molecule underlie the sensing capability and dominate the intensity and extent of applications of the nanopore approach. The volume exclusion model has been proposed and corrected to describe the nanopore current blockage. However, increasing evidence shows nonconformity with this model, suggesting that the ionic current within a nanopore should be entirely reconsidered. Here, we revisit the origin of nanopore current blockage from a ...[more]

PMID: 34467343

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Project description:The difficulty in characterizing ion conduction through membrane channels at the level of individual permeation events has made it challenging to elucidate the mechanistic principles underpinning this fundamental physiological process. Using long, all-atom simulations enabled by special-purpose hardware, we studied K(+) permeation across the KV1.2/2.1 voltage-gated potassium channel. At experimentally accessible voltages, which include the physiological range, the simulated permeation rate was substantially lower than the experimentally observed rate. The current-voltage relationship was also nonlinear but became linear at much higher voltages. We observed permeation consistent with a "knock-on" mechanism at all voltages. At high voltages, the permeation rate was in accordance with our previously reported KV1.2 pore-only simulations, after the simulated voltages from the previous study were recalculated using the correct method, new insight into which is provided here. Including the voltage-sensing domains in the simulated channel brought the linear current-voltage regime closer to the experimentally accessible voltages. The simulated permeation rate, however, still underestimated the experimental rate, because formation of the knock-on intermediate occurred too infrequently. Reducing the interaction strength between the ion and the selectivity filter did not increase conductance. In complementary simulations of gramicidin A, similar changes in interaction strength did increase the observed permeation rate. Permeation nevertheless remained substantially below the experimental value, largely because of infrequent ion recruitment into the pore lumen. Despite the need to apply large voltages to simulate the permeation process, the apparent voltage insensitivity of the permeation mechanism suggests that the direct simulation of permeation at the single-ion level can provide fundamental physiological insight into ion channel function. Notably, our simulations suggest that the knock-on permeation mechanisms in KV1.2 and KcsA may be different.

Dataset Information

Revisiting the Origin of Nanopore Current Blockage for Volume Difference Sensing at the Atomic Level.

Publications

Revisiting the Origin of Nanopore Current Blockage for Volume Difference Sensing at the Atomic Level.

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