Single-molecule fluorescence spectroscopy maps the folding landscape of a large protein

Menahem Pirchi, Guy Ziv, Inbal Riven, Sharona Sedghani Cohen, Nir Zohar, Yoav Barak and Gilad Haran ()
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Menahem Pirchi: Weizmann Institute of Science
Guy Ziv: Weizmann Institute of Science
Inbal Riven: Weizmann Institute of Science
Sharona Sedghani Cohen: Weizmann Institute of Science
Nir Zohar: Weizmann Institute of Science
Yoav Barak: Chemical Research Support, Weizmann Institute of Science
Gilad Haran: Weizmann Institute of Science

Nature Communications, 2011, vol. 2, issue 1, 1-7

Abstract: Abstract Proteins attain their function only after folding into a highly organized three-dimensional structure. Much remains to be learned about the mechanisms of folding of large multidomain proteins, which may populate metastable intermediate states on their energy landscapes. Here we introduce a novel method, based on high-throughput single-molecule fluorescence experiments, which is specifically geared towards tracing the dynamics of folding in the presence of a plethora of intermediates. We employ this method to characterize the folding reaction of a three-domain protein, adenylate kinase. Using thousands of single-molecule trajectories and hidden Markov modelling, we identify six metastable states on adenylate kinase's folding landscape. Remarkably, the connectivity of the intermediates depends on denaturant concentration; at low concentration, multiple intersecting folding pathways co-exist. We anticipate that the methodology introduced here will find broad applicability in the study of folding of large proteins, and will provide a more realistic scenario of their conformational dynamics.

Date: 2011
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DOI: 10.1038/ncomms1504

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