Force-dependent switch in protein unfolding pathways and transition-state movements

Proceedings of the National Academy of Sciences of the United States of America
Pavel I ZhuravlevD Thirumalai

Abstract

Although it is known that single-domain proteins fold and unfold by parallel pathways, demonstration of this expectation has been difficult to establish in experiments. Unfolding rate, [Formula: see text], as a function of force f, obtained in single-molecule pulling experiments on src SH3 domain, exhibits upward curvature on a [Formula: see text] plot. Similar observations were reported for other proteins for the unfolding rate [Formula: see text]. These findings imply unfolding in these single-domain proteins involves a switch in the pathway as f or [Formula: see text] is increased from a low to a high value. We provide a unified theory demonstrating that if [Formula: see text] as a function of a perturbation (f or [Formula: see text]) exhibits upward curvature then the underlying energy landscape must be strongly multidimensional. Using molecular simulations we provide a structural basis for the switch in the pathways and dramatic shifts in the transition-state ensemble (TSE) in src SH3 domain as f is increased. We show that a single-point mutation shifts the upward curvature in [Formula: see text] to a lower force, thus establishing the malleability of the underlying folding landscape. Our theory, applicable to any perturba...Continue Reading

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Citations

Mar 12, 2016·Proceedings of the National Academy of Sciences of the United States of America·Wenbing HuS Walter Englander
May 27, 2016·Proceedings of the National Academy of Sciences of the United States of America·Pavel I ZhuravlevD Thirumalai
May 27, 2016·Proceedings of the National Academy of Sciences of the United States of America·Saverio Alberti
Sep 19, 2016·Journal of Molecular Biology·Jörg SchönfelderRaul Perez-Jimenez
Oct 27, 2016·Journal of the American Chemical Society·Huabing WangMikael Oliveberg
Mar 25, 2017·The Journal of Physical Chemistry. a·Wolfgang QuappJordi Ribas-Ariño
Apr 30, 2017·The Journal of Physical Chemistry. B·Ronen BerkovichB J Berne
Aug 18, 2018·PLoS Computational Biology·Shishir AdhikariMichael Hinczewski
Aug 30, 2019·Proceedings of the National Academy of Sciences of the United States of America·Achim LöfJan Lipfert
Apr 9, 2020·Soft Matter·Aviel ChaimovichChristoph Dellago
Aug 25, 2016·Journal of Computational Chemistry·Wolfgang Quapp, Josep Maria Bofill
Nov 10, 2018·Proceedings of the National Academy of Sciences of the United States of America·Emily J GuinnSusan Marqusee
May 20, 2018·Physical Review. E·Fabio C ZegarraMargaret S Cheung
Jul 10, 2020·Physical Review. X·Andrei G GasicMargaret S Cheung
Apr 2, 2018·The Journal of Chemical Physics·Ngo Minh Toan, D Thirumalai
May 6, 2017·Protein Science : a Publication of the Protein Society·Kaixian LiuChristian M Kaiser
Nov 16, 2020·Protein Science : a Publication of the Protein Society·Cullen DemakisValerie Daggett
Feb 11, 2021·The Journal of Physical Chemistry. B·Pavel I ZhuravlevD Thirumalai
May 30, 2017·Journal of Molecular Biology·Hoi Sung Chung
Apr 6, 2016·Journal of Structural Biology·Shaon ChakrabartiD Thirumalai
Oct 8, 2019·Biophysical Journal·Janghyun YooHoi Sung Chung
May 12, 2021·The Journal of Physical Chemistry. B·Min-Kyung ChaeJeong-Man Park
Jul 29, 2021·The Journal of Physical Chemistry. B·Balaka MondalGovardhan Reddy
Aug 12, 2021·Physical Chemistry Chemical Physics : PCCP·Sergei F Chekmarev
Apr 21, 2017·The Journal of Physical Chemistry. B·Changbong Hyeon, D Thirumalai
Jan 6, 2018·The Journal of Physical Chemistry. B·Zhenxing Liu, D Thirumalai

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