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Energy Landscape of Ubiquitin Is Weakly Multidimensional

Mondal, B and Thirumalai, D and Reddy, G (2021) Energy Landscape of Ubiquitin Is Weakly Multidimensional. In: Journal of Physical Chemistry B .

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Official URL: https://doi.org/10.1021/acs.jpcb.1c02762


Single molecule pulling experiments report time-dependent changes in the extension (X) of a biomolecule as a function of the applied force (f). By fitting the data to one-dimensional analytical models of the energy landscape, we can extract the hopping rates between the folded and unfolded states in two-state folders as well as the height and the location of the transition state (TS). Although this approach is remarkably insightful, there are cases for which the energy landscape is multidimensional (catch bonds being the most prominent). To assess if the unfolding energy landscape in small single domain proteins could be one-dimensional, we simulated force-induced unfolding of ubiquitin (Ub) using the coarse-grained self-organized polymer-side chain (SOP-SC) model. Brownian dynamics simulations using the SOP-SC model reveal that the Ub energy landscape is weakly multidimensional (WMD), governed predominantly by a single barrier. The unfolding pathway is confined to a narrow reaction pathway that could be described as diffusion in a quasi-1D X-dependent free energy profile. However, a granular analysis using the Pfold analysis, which does not assume any form for the reaction coordinate, shows that X alone does not account for the height and, more importantly, the location of the TS. The f-dependent TS location moves toward the folded state as f increases, in accord with the Hammond postulate. Our study shows that, in addition to analyzing the f-dependent hopping rates, the transition state ensemble must also be determined without resorting to X as a reaction coordinate to describe the unfolding energy landscapes of single domain proteins, especially if they are only WMD. ©

Item Type: Journal Article
Publication: Journal of Physical Chemistry B
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to Authors
Keywords: Free energy; Ionic conduction; Location; Reaction rates, Brownian dynamics simulations; One dimensional analytical model; Polymer side-chains; Reaction coordinates; Reaction pathways; Single-domain proteins; Time-dependent changes; Transition state ensembles, Proteins
Department/Centre: Division of Chemical Sciences > Solid State & Structural Chemistry Unit
Date Deposited: 21 Nov 2021 16:27
Last Modified: 21 Nov 2021 16:27
URI: http://eprints.iisc.ac.in/id/eprint/69931

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