期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 6, 页码 2123-2128出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1216979110
关键词
atomistic simulations; denatured proteins; paramagnetic relaxation
资金
- National Science Foundation [MCB-0919860, MCB-1121867]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1051344] Funding Source: National Science Foundation
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [0919860, 1121867] Funding Source: National Science Foundation
The sizes of unfolded proteins under highly denaturing conditions scale as N-0.59 with chain length. This suggests that denaturing conditions mimic good solvents, whereby the preference for favorable chain-solvent interactions causes intrachain interactions to be repulsive, on average. Beyond this generic inference, the broader implications of N-0.59 scaling for quantitative descriptions of denatured state ensembles (DSEs) remain unresolved. Of particular interest is the degree to which N-0.59 scaling can simultaneously accommodate intrachain attractions and detectable long-range contacts. Here we present data showing that the DSE of the N-terminal domain of the L9 (NTL9) ribosomal protein in 8.3 Murea lacks detectable secondary structure and forms expanded conformations in accord with the expected N-0.59 scaling behavior. Paramagnetic relaxation enhancements, however, indicate the presence of detectable long-range contacts in the denatured-state ensemble of NTL9. To explain these observations we used atomistic thermal unfolding simulations to identify ensembles whose properties are consistent with all of the experimental observations, thus serving as useful proxies for the DSE of NTL9 in 8.3 M urea. Analysis of these ensembles shows that residual attractions are present under mimics of good solvent conditions, and for NTL9 they result from low-likelihood, medium/long-range contacts between hydrophobic residues. Our analysis provides a quantitative framework for the simultaneous observation of N-0.59 scaling and low-likelihood long-range contacts for the DSE of NTL9. We propose that such low-likelihood intramolecular hydrophobic clusters might be a generic feature of DSEs that play a gate-keeping role to protect against aggregation during protein folding.
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