title: Molecular dynamics simulations of DNA within a nanopore: arginine-phosphate tethering and a binding/sliding mechanism for translocation.
abstract: Protein nanopores show great potential as low-cost detectors in DNA sequencing devices. To date, research has largely focused on the staphylococcal pore α-hemolysin (αHL). In the present study, we have developed simplified models of the wild-type αHL pore and various mutants in order to study the translocation dynamics of single-stranded DNA under the influence of an applied electric field. The model nanopores reflect the experimentally measured conductance values in planar lipid bilayers. We show that interactions between rings of cationic amino acids and DNA backbone phosphates result in metastable tethering of nucleic acid molecules within the pore, leading us to propose a "binding and sliding" mechanism for translocation. We also observe folding of DNA into nonlinear conformational intermediates during passage through the confined nanopore environment. Despite adopting nonlinear conformations, the DNA hexamer always exits the pore in the same orientation as it enters (3' to 5') in our simulations. The observations from our simulations help to rationalize experimentally determined trends in residual current and translocation efficiency for αHL and its mutants.
authors.affiliation: Unilever Centre, Department of Chemistry, Lensfield Road, University of Cambridge, Cambridge CB2 1EW, U.K.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Guy
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Heron
authors.forename: Hagan
authors.initials: H
authors.lastname: Bayley
authors.forename: Syma
authors.initials: S
authors.lastname: Khalid
mesh_terms: D001120:Arginine / Q000737:chemistry*; D015374:Biosensing Techniques; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D004573:Electrolytes; D029968:Escherichia coli Proteins / Q000737:chemistry; D006460:Hemolysin Proteins / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D058608:Nanopores; D036103:Nanotechnology / Q000379:methods*; D010710:Phosphates / Q000737:chemistry*; D011485:Protein Binding; D021381:Protein Transport; D013211:Staphylococcus aureus / Q000378:metabolism
chemical_list: D004573:Electrolytes; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D010710:Phosphates; D004247:DNA; D001120:Arginine