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Biomolecular dynamics: order-disorder transitions and energy landscapes.

ABSTRACT: While the energy landscape theory of protein folding is now a widely accepted view for understanding how relatively weak molecular interactions lead to rapid and cooperative protein folding, such a framework must be extended to describe the large-scale functional motions observed in molecular machines. In this review, we discuss (1) the development of the energy landscape theory of biomolecular folding, (2) recent advances toward establishing a consistent understanding of folding and function and (3) emerging themes in the functional motions of enzymes, biomolecular motors and other biomolecular machines. Recent theoretical, computational and experimental lines of investigation have provided a very dynamic picture of biomolecular motion. In contrast to earlier ideas, where molecular machines were thought to function similarly to macroscopic machines, with rigid components that move along a few degrees of freedom in a deterministic fashion, biomolecular complexes are only marginally stable. Since the stabilizing contribution of each atomic interaction is on the order of the thermal fluctuations in solution, the rigid body description of molecular function must be revisited. An emerging theme is that functional motions encompass order-disorder transitions and structural flexibility provides significant contributions to the free energy. In this review, we describe the biological importance of order-disorder transitions and discuss the statistical-mechanical foundation of theoretical approaches that can characterize such transitions.

SUBMITTER: Whitford PC

PROVIDER: S-EPMC3695400 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Biomolecular dynamics: order-disorder transitions and energy landscapes.

Whitford Paul C PC Sanbonmatsu Karissa Y KY Onuchic José N JN

Reports on progress in physics. Physical Society (Great Britain) 20120628 7

While the energy landscape theory of protein folding is now a widely accepted view for understanding how relatively weak molecular interactions lead to rapid and cooperative protein folding, such a framework must be extended to describe the large-scale functional motions observed in molecular machines. In this review, we discuss (1) the development of the energy landscape theory of biomolecular folding, (2) recent advances toward establishing a consistent understanding of folding and function an ...[more]

PMID: 22790780

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Project description:For disordered proteins, ligand binding can be a critical event that changes their structural dynamics. The ability to characterize such changes would facilitate the development of drugs designed to stabilize disordered proteins, whose mis-folding is important for a number of pathologies, including neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular dynamics (MD) simulations to characterize the structural changes in disordered proteins that result from ligand binding. We show here that both an ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P, are disordered, yet exhibit structures that are distinct from chemically denatured unfolded states in solution, and that they undergo transitions to a more structured state upon ligand binding. These systems may serve as models for the characterization of ligand-induced disorder-to-order transitions in proteins using structural proteomics approaches. SIGNIFICANCE: In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular-dynamics simulations to characterize the structural changes in disordered proteins that result from ligand binding. The protein-ligand systems studied here (the ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P) may serve as models for understanding ligand-induced disorder-to-order transitions in proteins. Additionally, the structural proteomic techniques demonstrated here are shown to be effective tools for the characterization of disorder-to-order transitions and can be used to facilitate study of other systems in which this class of structural transition can be used for modulating major pathological features of disease, such as the abnormal protein aggregation that occurs with Parkinson's disease and Alzheimer's disease.

Dataset Information

Biomolecular dynamics: order-disorder transitions and energy landscapes.

Publications

Biomolecular dynamics: order-disorder transitions and energy landscapes.

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