Abstract
The transport of molecules through nanoscale confined space is relevant in biology, biosensing, and industrial filtration. Microscopically modeling transport through nanopores is required for a fundamental understanding and guiding engineering, but the short duration and low replica number of existing simulation approaches limit statistically relevant insight. Here we explore protein transport in nanopores with a high-throughput computational method that realistically simulates hundreds of up to seconds-long protein trajectories by combining Brownian dynamics and continuum simulation and integrating both driving forces of electroosmosis and electrophoresis. Ionic current traces are computed to enable experimental comparison. By examining three biological and synthetic nanopores, our study answers questions about the kinetics and mechanism of protein transport and additionally reveals insight that is inaccessible from experiments yet relevant for pore design. The discovery of extremely frequent unhindered passage can guide the improvement of biosensor pores to enhance desired biomolecular recognition by pore-tethered receptors. Similarly, experimentally invisible nontarget adsorption to pore walls highlights how to improve recently developed DNA nanopores. Our work can be expanded to pressure-driven flow to model industrial nanofiltration processes.
Highlights
The transport of molecules through nanoscale confined space is relevant in biology, biosensing, and industrial filtration
Transport is influenced by electrostatics and hydrodynamics, which can vary within the channel lumen.[16−22] Nanoscale transport is best studied with resistive-pulse sensing, where individual molecules passing through the nanopore are registered via temporal changes of a transmembrane ion current, as used in DNA sequencing[10,11,13] and single-molecule protein sensing.[12,23]
The experiments do not offer a dynamic picture of the detailed transport processes, leaving several key questions unanswered: What is the trajectory of a protein entering a channel and what is the probability that the molecule binds to a recognition site rather than passing the nanopore? does binding to a recognition site follow the strength expected from solution studies, and what is the extent and nature of nonspecific binding to a channel wall?
Summary
The transport of molecules through nanoscale confined space is relevant in biology, biosensing, and industrial filtration. Transport is influenced by electrostatics and hydrodynamics, which can vary within the channel lumen.[16−22] Nanoscale transport is best studied with resistive-pulse sensing, where individual molecules passing through the nanopore are registered via temporal changes of a transmembrane ion current, as used in DNA sequencing[10,11,13] and single-molecule protein sensing.[12,23] Yet, the experiments do not offer a dynamic picture of the detailed transport processes, leaving several key questions unanswered: What is the trajectory of a protein entering a channel and what is the probability that the molecule binds to a recognition site rather than passing the nanopore? One approach to bypass long time scales is steered MD, where a molecule is forced to translocate with artificially high speed in nanoseconds.[24,25,37] But this does not yield the true distribution of event durations and may distort the description of physical processes
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