Abstract
Single-molecule studies of protein folding hold keys to unveiling protein folding pathways and elusive intermediate folding states - attractive pharmaceutical targets. Although conventional single-molecule approaches can detect folding intermediates, they presently lack throughput and require elaborate labeling. Here, we theoretically show that measurements of ionic current through a nanopore containing a protein can report on the protein's folding state. Our all-atom molecular dynamics (MD) simulations show that the unfolding of a protein lowers the nanopore ionic current, an effect that originates from the reduction of ion mobility in proximity to a protein. Using a theoretical model, we show that the average change in ionic current produced by a folding-unfolding transition is detectable despite the orientational and conformational heterogeneity of the folded and unfolded states. By analyzing millisecond-long all-atom MD simulations of multiple protein transitions, we show that a nanopore ionic current recording can detect folding-unfolding transitions in real time and report on the structure of folding intermediates.
Original language | English (US) |
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Pages (from-to) | 7091-7100 |
Number of pages | 10 |
Journal | ACS Nano |
Volume | 11 |
Issue number | 7 |
DOIs | |
State | Published - Jul 25 2017 |
Keywords
- folding intermediates
- ionic current
- misfolding
- molecular dynamics
- nanopore
- protein folding
ASJC Scopus subject areas
- General Materials Science
- General Engineering
- General Physics and Astronomy