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Unfolded states under folding conditions accommodate sequence-specific conformational preferences with random coil-like dimensions

2019; National Academy of Sciences; Volume: 116; Issue: 25 Linguagem: Inglês

10.1073/pnas.1818206116

1091-6490

Ivan Peran, Alex S. Holehouse, Isaac S. Carrico, Rohit V. Pappu, Osman Bilsel, Daniel P. Raleigh,

RNA and protein synthesis mechanisms

Significance The tools of structural biology afford high-resolution descriptions of folded states of proteins. However, an atomic-level description of unfolded states under folding conditions has remained elusive. Challenges arise from the pronounced conformational heterogeneity and the very low population of unfolded states under folding conditions. We have combined a series of time-resolved biophysical experiments with all-atom simulations and polymer theory to obtain a high-resolution description of unfolded ensembles under folding conditions. These unfolded states are characterized by discernible sequence-specific conformational preferences. These preferences are averaged over by conformational fluctuations, giving rise to ensemble-averaged properties that are consistent with those of canonical random coils. Our findings are relevant to understanding functional and pathological interactions involving unfolded forms of proteins.