Unlocking the unfolded structure of ubiquitin: Combining time-resolved x-ray solution scattering and molecular dynamics to generate unfolded ensembles.

Autor:	Nijhawan AK; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA., Leshchev D; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA., Hsu DJ; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA., Chan AM; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA., Rimmerman D; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA., Hong J; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA., Kosheleva I; Center for Advanced Radiation Sources, The University of Chicago, Chicago, Illinois 60637, USA., Henning R; Center for Advanced Radiation Sources, The University of Chicago, Chicago, Illinois 60637, USA., Kohlstedt KL; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA., Chen LX; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA.
Jazyk:	angličtina
Zdroj:	The Journal of chemical physics [J Chem Phys] 2024 Jul 21; Vol. 161 (3).
DOI:	10.1063/5.0217013
Abstrakt:	The unfolding dynamics of ubiquitin were studied using a combination of x-ray solution scattering (XSS) and molecular dynamics (MD) simulations. The kinetic analysis of the XSS ubiquitin signals showed that the protein unfolds through a two-state process, independent of the presence of destabilizing salts. In order to characterize the ensemble of unfolded states in atomic detail, the experimental XSS results were used as a constraint in the MD simulations through the incorporation of x-ray scattering derived potential to drive the folded ubiquitin structure toward sampling unfolded states consistent with the XSS signals. We detail how biased MD simulations provide insight into unfolded states that are otherwise difficult to resolve and underscore how experimental XSS data can be combined with MD to efficiently sample structures away from the native state. Our results indicate that ubiquitin samples unfolded in states with a high degree of loss in secondary structure yet without a collapse to a molten globule or fully solvated extended chain. Finally, we propose how using biased-MD can significantly decrease the computational time and resources required to sample experimentally relevant nonequilibrium states. (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)
Databáze:	MEDLINE
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