High-Resolution Mapping of the Folding Transition State of a WW Domain.

Journal of Molecular Biology
Kapil DaveMartin Gruebele

Abstract

Fast-folding WW domains are among the best-characterized systems for comparing experiments and simulations of protein folding. Recent microsecond-resolution experiments and long duration (totaling milliseconds) single-trajectory modeling have shown that even mechanistic changes in folding kinetics due to mutation can now be analyzed. Thus, a comprehensive set of experimental data would be helpful to benchmark the predictions made by simulations. Here, we use T-jump relaxation in conjunction with protein engineering and report mutational Φ-values (Φ(M)) as indicators for folding transition-state structure of 65 side chain, 7 backbone hydrogen bond, and 6 deletion and /or insertion mutants within loop 1 of the 34-residue hPin1 WW domain. Forty-five cross-validated consensus mutants could be identified that provide structural constraints for transition-state structure within all substructures of the WW domain fold (hydrophobic core, loop 1, loop 2, β-sheet). We probe the robustness of the two hydrophobic clusters in the folding transition state, discuss how local backbone disorder in the native-state can lead to non-classical Φ(M)-values (Φ(M) > 1) in the rate-determining loop 1 substructure, and conclusively identify mutations an...Continue Reading

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Citations

Apr 26, 2016·The Journal of Physical Chemistry. B·Nandakumar RajasekaranAthi N Naganathan
Jun 2, 2016·Journal of the American Chemical Society·Che-Hsiung HsuJeffery W Kelly
Jun 28, 2003·Biophysical Journal·Weihua GuoJoan-Emma Shea
Jul 27, 2017·Physical Chemistry Chemical Physics : PCCP·Soundhararajan GopiAthi N Naganathan
Jan 17, 2020·The Journal of Chemical Physics·Hongbin Wan, Vincent A Voelz
Mar 10, 2021·The Journal of Physical Chemistry. B·Taisong ZouSefika Banu Ozkan
Jun 25, 2021·The Journal of Physical Chemistry. B·Myung Keun ChoSihyun Ham
Apr 22, 2016·The Journal of Physical Chemistry Letters·Shahar SukenikMartin Gruebele
Jul 21, 2017·Accounts of Chemical Research·Maziar S ArdejaniJeffery W Kelly
Jul 10, 2019·The Journal of Physical Chemistry. B·Martin Culka, Lubomír Rulíšek
Apr 10, 2020·The Journal of Physical Chemistry. B·Khatuna KachlishviliGia G Maisuradze

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