Functional roles of enzyme dynamics in accelerating active site chemistry: Emerging techniques and changing concepts

Gao, Shuaihua; Klinman, Judith P.

doi:10.1016/j.sbi.2022.102434

Cited by 23 publications

(14 citation statements)

References 87 publications

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“…2, collisions with solvent underlie the activation of chemical reactions in condensed phase and this will occur in a largely isotropic manner for small, solvated reactants [30]. By contrast, the anisotropic structures of globular proteins introduce the likelihood of privileged protein pathways for productive heat transfer [30]. Huge kinetic isotope effects (e.g.…”

Section: Temperature-dependent Properties Of Enzyme-catalysed Reactionsmentioning

confidence: 99%

Dynamical activation of function in metalloenzymes

Klinman

2022

FEBS Letters

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Formulations of hydrogen tunneling in enzyme‐catalysed C–H activation reactions indicate enthalpic barriers to reaction that are independent of chemical steps and dependent on the protein scaffold. A tool to identify catalytically relevant site‐specific protein thermal networks has emerged from temperature‐dependent hydrogen deuterium exchange (TDHDX). Focusing on mutant enzyme forms with altered activation energies for catalysis, TDHDX provides a comparative analysis of the impact of mutation on Ea for local protein unfolding. Identified thermal networks appear unrelated to protein scaffold conservation and track to the dictates of the catalysed reaction, including sites for metal binding. The positions of thermal networks provide a framework for further understanding of time‐dependent, functionally relevant protein motions. Measurement of nanosecond Stokes shifts at the surface of the thermal network in soybean lipoxygenase yields activation energies that are identical to Ea values measured for kcat. This finding identifies a rapid (> nanosecond), long‐range and cooperative structural reorganization as the thermal barrier to catalysis. A model for protein dynamics is put forward that integrates broadly distributed protein conformational sampling with protein embedded thermal networks.

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Section: Temperature-dependent Properties Of Enzyme-catalysed Reactionsmentioning

confidence: 99%

Dynamical activation of function in metalloenzymes

Klinman

2022

FEBS Letters

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“…Temperature dependent HDX is becoming more prevalent for its ability to provide additional insight into the role of protein fluctuations and their relevance to function, over conventional HDX analysis at a single temperature. [43][44][45] Based on pattern recognition, three classes of temperature dependent HDX behaviour emerged (Fig. 2A-C).…”

Section: Resultsmentioning

confidence: 99%

Chorography and conformational dynamism of the Soluble Human Fibrinogen in solution

Şen

Hudson²,

Offenbacher

et al. 2022

Preprint

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Fibrinogen is a soluble, multi-subunit and multi-domain dimeric protein, which, upon its proteolytic cleavage by thrombin, is converted to insoluble fibrin initiating polymerization that substantially contributes to clot growth. The consentaneous structural view of the soluble form of fibrinogen is relatively straight and rigid-like. However, fibrinogen contains numerous, transiently-accessible "cryptic" epitopes for hemostatic and immunologic proteins, suggesting that fibrinogen exhibits conformational flexibility, which may play functional roles in its temporal and spatial interactions. Hitherto, there has been limited information on the solution structure and internal flexibility of soluble fibrinogen. Here, utilizing an integrative, biophysical approach involving temperature-dependent hydrogen-deuterium exchange mass spectrometry, small angle X-ray scattering, and negative stain electron microscopy, we present a holistic, conformationally dynamic model of human fibrinogen in solution. Our data reveal a high degree of internal flexibility, accommodated by four major and distinct flexible sites along the central axis of the protein. We propose that the fibrinogen structure in solution consists of a complex, conformational landscape with multiple local minima, rather than a single, rigid topology. This is further supported by the location of numerous point mutations that are linked to dysfibrinogenemia, and post-translational modifications, residing near fibrinogen flexions. This work provides a molecular basis for the structural "dynamism" of fibrinogen that is expected to influence the broad swath of functionally diverse macromolecular interactions and fine-tune the structural and mechanical properties of blood clots.

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“…In the current era when efficient energy conversion is of paramount importance, optimizing thermal transport in both classical and quantum systems has become a topic of intense theoretical and experimental interest for nanotechnology 58 , 59 . Furthermore, the possibility of realizing thermal conduits in various biological systems have been proposed to optimize thermal networks and information transfer 60 , 61 . Transient reverse heat flow in these contexts may confer biological machinery with enhanced functionality for energy harvesting.…”

Section: Discussionmentioning

confidence: 99%

Nonreciprocal forces enable cold-to-hot heat transfer between nanoparticles

Loos

Arabha

Rajabpour

et al. 2023

Sci Rep

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We study the heat transfer between two nanoparticles held at different temperatures that interact through nonreciprocal forces, by combining molecular dynamics simulations with stochastic thermodynamics. Our simulations reveal that it is possible to construct nano refrigerators that generate a net heat transfer from a cold to a hot reservoir at the expense of power exerted by the nonreciprocal forces. Applying concepts from stochastic thermodynamics to a minimal underdamped Langevin model, we derive exact analytical expressions predictions for the fluctuations of work, heat, and efficiency, which reproduce thermodynamic quantities extracted from the molecular dynamics simulations. The theory only involves a single unknown parameter, namely an effective friction coefficient, which we estimate fitting the results of the molecular dynamics simulation to our theoretical predictions. Using this framework, we also establish design principles which identify the minimal amount of entropy production that is needed to achieve a certain amount of uncertainty in the power fluctuations of our nano refrigerator. Taken together, our results shed light on how the direction and fluctuations of heat flows in natural and artificial nano machines can be accurately quantified and controlled by using nonreciprocal forces.

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Functional roles of enzyme dynamics in accelerating active site chemistry: Emerging techniques and changing concepts

Cited by 23 publications

References 87 publications

Dynamical activation of function in metalloenzymes

Dynamical activation of function in metalloenzymes

Chorography and conformational dynamism of the Soluble Human Fibrinogen in solution

Nonreciprocal forces enable cold-to-hot heat transfer between nanoparticles

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