期刊
ACS NANO
卷 11, 期 7, 页码 7091-7100出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.7b02718
关键词
nanopore; protein folding ionic current; molecular dynamics; folding intermediates; misfolding
类别
资金
- National Institutes of Health [R01-HG007406]
- China Scholarship Council [CSC201506090040]
- National Natural Science Foundation of China [51435003]
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.
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