Identification of the Minimal Protein-Folding Nucleus through Loop-Entropy Perturbations

To explore the plasticity and structural constraints of the proteinfolding nucleus we have constructed through circular permutation four topological variants of the ribosomal protein S6. In effect, these topological variants represent entropy mutants with maintained spatial contacts. The proteins we...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-03, Vol.103 (11), p.4083-4088
Main Authors: Lindberg, Magnus O., Haglund, Ellinor, Hubner, Isaac A., Shakhnovich, Eugene I., Oliveberg, Mikael
Format: Article
Language:English
Subjects:
Biochemistry
Biokemi
Biological Sciences
Biophysical Phenomena
Biophysics
Chemistry
circular permutations
Correlations
Entropy
In Vitro Techniques
Kemi
Kinetics
MEDICIN
MEDICINE
Models, Molecular
Mutation
Nucleation
phi-values
Protein Conformation
Protein Folding
Protein refolding
Proteins
Ribosomal Protein S6 - chemistry
Ribosomal Protein S6 - genetics
Thermodynamics
Topology
Trajectories
transition state
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Summary:To explore the plasticity and structural constraints of the proteinfolding nucleus we have constructed through circular permutation four topological variants of the ribosomal protein S6. In effect, these topological variants represent entropy mutants with maintained spatial contacts. The proteins were characterized at two complementary levels of detail: by ø-value analysis estimating the extent of contact formation in the transition-state ensemble and by Hammond analysis measuring the site-specific growth of the folding nucleus. The results show that, although the loop-entropy alterations markedly influence the appearance and structural location of the folding nucleus, it retains a common motif of one helix docking against two strands. This nucleation motif is built around a shared subset of side chains in the center of the hydrophobic core but extends in different directions of the S6 structure following the permutant-specific differences in local loop entropies. The adjustment of the critical folding nucleus to alterations in loop entropies is reflected by a direct correlation between the ϕ-value change and the accompanying change in local sequence separation.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.0508863103