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Single-stranded DNA within nanopores: conformational dynamics and implications for sequencing; a molecular dynamics simulation study.

ABSTRACT: Engineered protein nanopores, such as those based on ?-hemolysin from Staphylococcus aureus have shown great promise as components of next-generation DNA sequencing devices. However, before such protein nanopores can be used to their full potential, the conformational dynamics and translocation pathway of the DNA within them must be characterized at the individual molecule level. Here, we employ atomistic molecular dynamics simulations of single-stranded DNA movement through a model ?-hemolysin pore under an applied electric field. The simulations enable characterization of the conformations adopted by single-stranded DNA, and allow exploration of how the conformations may impact on translocation within the wild-type model pore and a number of mutants. Our results show that specific interactions between the protein nanopore and the DNA can have a significant impact on the DNA conformation often leading to localized coiling, which in turn, can alter the order in which the DNA bases exit the nanopore. Thus, our simulations show that strategies to control the conformation of DNA within a protein nanopore would be a distinct advantage for the purposes of DNA sequencing.

SUBMITTER: Guy AT

PROVIDER: S-EPMC3433622 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Single-stranded DNA within nanopores: conformational dynamics and implications for sequencing; a molecular dynamics simulation study.

Guy Andrew T AT Piggot Thomas J TJ Khalid Syma S

Biophysical journal 20120901 5

Engineered protein nanopores, such as those based on α-hemolysin from Staphylococcus aureus have shown great promise as components of next-generation DNA sequencing devices. However, before such protein nanopores can be used to their full potential, the conformational dynamics and translocation pathway of the DNA within them must be characterized at the individual molecule level. Here, we employ atomistic molecular dynamics simulations of single-stranded DNA movement through a model α-hemolysin ...[more]

PMID: 23009852

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Project description:The integration of local heat sources with solid-state nanopores offers new means for controlling the transmembrane transport of charged biomacromolecules. In the case of electrophoretic transport of DNA, recent experimental studies revealed unexpected temperature dependences of the DNA capture rate, the DNA translocation velocity, and the ionic current blockades produced by the presence of DNA in the nanopore. Here, we report the results of all-atom molecular dynamics simulations that elucidated the effect of temperature on the key microscopic processes governing electric field-driven transport of DNA through nanopores. Mimicking the experimental setup, we simulated the capture and subsequent translocation of short DNA duplexes through a locally heated nanopore at several temperatures and electrolyte conditions. The temperature dependence of ion mobility at the DNA surface was found to cause the dependence of the relative conductance blockades on temperature. To the first order, the effective force on DNA in the nanopore was found to be independent of temperature, despite a considerable reduction of solution viscosity. The temperature dependence of the solution viscosity was found to make DNA translocations faster for a uniformly heated system but not in the case of local heating that does not affect viscosity of solution surrounding the untranslocated part of the molecule. Increasing solution temperature was also found to reduce the lifetime of bonds formed between cations and DNA. Using a flow suppression algorithm, we were able to separate the effects of electro-osmotic flow and direct ion binding, finding the reduced durations of DNA-ion bonds to increase, albeit weakly, the effective force experienced by DNA in an electric field. Unexpectedly, our simulations revealed a considerable temperature dependence of solvent velocity at the DNA surface-slip velocity, an effect that can alter hydrodynamic coupling between the motion of DNA and the surrounding fluid.

Dataset Information

Single-stranded DNA within nanopores: conformational dynamics and implications for sequencing; a molecular dynamics simulation study.

Publications

Single-stranded DNA within nanopores: conformational dynamics and implications for sequencing; a molecular dynamics simulation study.

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