Energy landscape in molecular glasses probed by high-resolution dielectric experiments

Biomolecular folding involves searching among myriad possibilities for the native conformation, but the elementary steps expected from theory for this search have never been detected directly. We probed the dynamics of folding at high resolution using optical tweezers, measuring individual trajectories as nucleic acid hairpins passed through the high-energy transition states that dominate kinetics and define folding mechanisms. We observed brief but ubiquitous pauses in the transition states, with a dwell time distribution that matched microscopic theories of folding quantitatively. The sequence dependence suggested that pauses were dominated by microbarriers from nonnative conformations during the search by each nucleotide residue for the native base-pairing conformation. Furthermore, the pauses were position dependent, revealing subtle local variations in energy–landscape roughness and allowing the diffusion coefficient describing the microscopic dynamics within the barrier to be found without reconstructing the shape of the energy landscape. These results show how high-resolution measurements can elucidate key microscopic events during folding to test fundamental theories of folding.

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High-resolution free energy landscape analysis of protein folding

Biochemical Society Transactions ◽

10.1042/bst20140260 ◽

2015 ◽

Vol 43 (2) ◽

pp. 157-161 ◽

Cited By ~ 1

Author(s):

Polina V. Banushkina ◽

Sergei V. Krivov

Keyword(s):

Free Energy ◽

Protein Folding ◽

High Resolution ◽

Energy Landscape ◽

Quantitative Description ◽

Free Energy Landscape ◽

Transition Path ◽

Exponential Factor ◽

Basic Properties ◽

Folding Dynamics

The free energy landscape can provide a quantitative description of folding dynamics, if determined as a function of an optimally chosen reaction coordinate. The profile together with the optimal coordinate allows one to directly determine such basic properties of folding dynamics as the configurations of the minima and transition states, the heights of the barriers, the value of the pre-exponential factor and its relation to the transition path times. In the present study, we review the framework, in particular, the approach to determine such an optimal coordinate, and its application to the analysis of simulated protein folding dynamics.

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Diffusion of a disordered protein on its folded ligand

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2106690118 ◽

2021 ◽

Vol 118 (37) ◽

pp. e2106690118

Author(s):

Felix Wiggers ◽

Samuel Wohl ◽

Artem Dubovetskyi ◽

Gabriel Rosenblum ◽

Wenwei Zheng ◽

...

Keyword(s):

High Resolution ◽

Single Molecule ◽

Intrinsically Disordered Proteins ◽

Energy Landscape ◽

Binding Kinetics ◽

Disordered Proteins ◽

Adhesion Protein ◽

Intrinsically Disordered ◽

Disordered Protein ◽

High Affinity

Intrinsically disordered proteins often form dynamic complexes with their ligands. Yet, the speed and amplitude of these motions are hidden in classical binding kinetics. Here, we directly measure the dynamics in an exceptionally mobile, high-affinity complex. We show that the disordered tail of the cell adhesion protein E-cadherin dynamically samples a large surface area of the protooncogene β-catenin. Single-molecule experiments and molecular simulations resolve these motions with high resolution in space and time. Contacts break and form within hundreds of microseconds without a dissociation of the complex. The energy landscape of this complex is rugged with many small barriers (3 to 4 kBT) and reconciles specificity, high affinity, and extreme disorder. A few persistent contacts provide specificity, whereas unspecific interactions boost affinity.

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High-Resolution Patterning of Molecular Glasses Using Supercritical Carbon Dioxide

Advanced Materials ◽

10.1002/adma.200501802 ◽

2006 ◽

Vol 18 (4) ◽

pp. 442-446 ◽

Cited By ~ 33

Author(s):

N. M. Felix ◽

K. Tsuchiya ◽

C. K. Ober

Keyword(s):

Carbon Dioxide ◽

High Resolution ◽

Supercritical Carbon Dioxide ◽

Molecular Glasses ◽

Supercritical Carbon

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Molecular Glasses with High Fictive Temperatures for Energy Landscape Evaluations

The Journal of Physical Chemistry B ◽

10.1021/jp012001z ◽

2002 ◽

Vol 106 (5) ◽

pp. 1069-1080 ◽

Cited By ~ 19

Author(s):

V. Velikov ◽

S. Borick ◽

C. A. Angell

Keyword(s):

Energy Landscape ◽

Molecular Glasses

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Nature of excitations and defects in structural glasses

Nature Communications ◽

10.1038/s41467-019-13010-x ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Camille Scalliet ◽

Ludovic Berthier ◽

Francesco Zamponi

Keyword(s):

Amorphous Materials ◽

Energy Landscape ◽

Three Dimensional ◽

Collective Excitations ◽

Molecular Glasses ◽

Physical Conditions ◽

Temperature Scales ◽

Model Glass ◽

Localized Defects ◽

Glassy Materials

Abstract The nature of defects in amorphous materials, analogous to vacancies and dislocations in crystals, remains elusive. Here, we explore their nature in a three-dimensional microscopic model glass-former that describes granular, colloidal, atomic and molecular glasses by changing the temperature and density. We find that all glasses evolve in a very rough energy landscape, with a hierarchy of barrier sizes corresponding to both localized and delocalized excitations. Collective excitations dominate in the jamming regime relevant for granular and colloidal glasses. By moving gradually to larger densities describing atomic and molecular glasses, the system crosses over to a regime dominated by localized defects and relatively simpler landscapes. We quantify the energy and temperature scales associated to these defects and their evolution with density. Our results pave the way to a systematic study of low-temperature physics in a broad range of physical conditions and glassy materials.

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