Metastability of Protein Solution Structures in the Absence of a Solvent: Rugged Energy Landscape and Glass-like Behavior

• DOI: 10.1021/jacs.3c12892
• Publication Date: 2024-04-10T18:17:56Z
• Authors: Tyler. C. Cropley; Fanny. C. Liu; Mengqi Chai; Matthew F. Bush; Christian Bleiholder
• Keywords: Ion-mobility spectrometry; Energy landscape; Metastability

Native ion mobility/mass spectrometry is well-poised to structurally screen proteomes but characterizes protein structures in the absence of a solvent. This raises long-standing unanswered questions about biological significance identified through spectrometry. Using newly developed computational and experimental mobility/ion methods, we investigate unfolding ubiquitin solvent-free environment. Our data suggest that folded, observed by exists largely native fold with an intact β-grasp motif α-helix. The ensemble ions can be partitioned into kinetically stable subpopulations appear correspond structural heterogeneity solution. Time-resolved measurements show exhibits strongly stretched-exponential time dependence, which simulations trace rugged energy landscape kinetic traps. Unfolding rate constants are estimated approximately 800 20,000 times smaller than presence water, effectively quenching process on scale typical measurements. proposed pathway shares substantial characteristics established for solvent, including polarized transition state significant content N-terminal β-hairpin (1) governing motions proteins analogy glassy systems; (2) large-scale may at least partially determined amino acid sequence polypeptide chain; (3) solvent facilitates, rather controls, motions.