Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 25, Pages 12301-12310Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1818206116
Keywords
protein folding; unfolded state; FRET; compaction transition
Categories
Funding
- Wellcome Trust [107927/Z/15/Z]
- US National Science Foundation (NSF) [IDBR 1353942, MCB 0721312, MCB-1614766]
- Human Frontiers Science Program [RGP0034/2017]
- NSF [MCB-1330259, MCB 1051344]
- DOE Office of Science [DE-AC02-06CH11357]
- National Institute of General Medical Sciences of the National Institutes of Health [9 P41 GM103622]
- Wellcome Trust [107927/Z/15/Z] Funding Source: Wellcome Trust
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Proteins are marginally stable molecules that fluctuate between folded and unfolded states. Here, we provide a high-resolution description of unfolded states under refolding conditions for the N-terminal domain of the L9 protein (NTL9). We use a combination of time-resolved Forster resonance energy transfer (FRET) based on multiple pairs of minimally perturbing labels, time-resolved small-angle X-ray scattering (SAXS), all-atom simulations, and polymer theory. Upon dilution from high denaturant, the unfolded state undergoes rapid contraction. Although this contraction occurs before the folding transition, the unfolded state remains considerably more expanded than the folded state and accommodates a range of local and nonlocal contacts, including secondary structures and native and nonnative interactions. Paradoxically, despite discernible sequence-specific conformational preferences, the ensemble-averaged properties of unfolded states are consistent with those of canonical random coils, namely polymers in indifferent (theta) solvents. These findings are concordant with theoretical predictions based on coarse-grained models and inferences drawn from single-molecule experiments regarding the sequence-specific scaling behavior of unfolded proteins under folding conditions.
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