Dynamic disorder can explain non-exponential kinetics of fast protein mechanical unfolding

Costescu, Bogdan I.; Sturm, Sebastian; Gräter, Frauke

doi:10.1016/j.jsb.2016.10.003

Cited by 10 publications

(8 citation statements)

References 36 publications

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“…In consequence, If the tension on the termini modified the conformational dynamics of the loop, we consider its effect on the accessibility only to be small. The use of a high force in fact accelerated the kinetics of the unfolding process, but the rates and unfolding pathways can be reconciled with those obtained at low (or zero) force as determined in our recent publication for another protein 34 . For all these reasons we think that although the pulling protocol (in particular the magnitude of the applied force) drastically modulate the kinetics of the process, it may not substantially change our findings about the resultant isomerization-prone conformations and their populations.…”

Section: Discussionmentioning

confidence: 55%

Accessibility explains preferred thiol-disulfide isomerization in a protein domain

Kolšek

Aponte-Santamaría

Gräter

2017

Sci Rep

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Disulfide bonds are key stabilizing and yet potentially labile cross-links in proteins. While spontaneous disulfide rearrangement through thiol-disulfide exchange is increasingly recognized to play an important physiological role, its molecular determinants are still largely unknown. Here, we used a novel hybrid Monte Carlo and Molecular Dynamics scheme to elucidate the molecular principles of thiol-disulfide exchange in proteins, for a mutated immunoglobulin domain as a model system. Unexpectedly, using simple proximity as the criterion for thiol-disulfide exchange, our method correctly predicts the experimentally observed regiospecificity and selectivity of the cysteine-rich protein. While redox reactivity has been examined primarily on the level of transition states and activation barriers, our results argue for accessibility of the disulfide by the attacking thiol given the highly dynamic and sterically demanding protein as a major bottleneck of thiol-disulfide exchange. This scenario may be similarly at play in other proteins with or without an evolutionarily designed active site.

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Section: Discussionmentioning

confidence: 55%

Accessibility explains preferred thiol-disulfide isomerization in a protein domain

Kolšek

Aponte-Santamaría

Gräter

2017

Sci Rep

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“…Hence, measured transition rates are mostly dependent on the height of the energy barrier between native and unfolded, but still collapsed, states. In this regard, more complex free energy models account for coordinate reactions that are not directly observable in experiments (Dudko et al 2008 ) or for the heterogeneity of transition paths due to static and dynamic disorder (Costescu et al 2017 ; Kuo et al 2010 ). Theoretical developments have also been extended to serially linked arrays of domains, a configuration found in many proteins with mechanical roles (Berkovich et al 2018 ; Chetrit et al 2020 ; Valle-Orero et al 2015 ).…”

Section: The Free Energy Of a Protein Under Forcementioning

confidence: 99%

Protein nanomechanics in biological context

Alegre-Cebollada

2021

Biophys Rev

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How proteins respond to pulling forces, or protein nanomechanics, is a key contributor to the form and function of biological systems. Indeed, the conventional view that proteins are able to diffuse in solution does not apply to the many polypeptides that are anchored to rigid supramolecular structures. These tethered proteins typically have important mechanical roles that enable cells to generate, sense, and transduce mechanical forces. To fully comprehend the interplay between mechanical forces and biology, we must understand how protein nanomechanics emerge in living matter. This endeavor is definitely challenging and only recently has it started to appear tractable. Here, I introduce the main in vitro single-molecule biophysics methods that have been instrumental to investigate protein nanomechanics over the last 2 decades. Then, I present the contemporary view on how mechanical force shapes the free energy of tethered proteins, as well as the effect of biological factors such as post-translational modifications and mutations. To illustrate the contribution of protein nanomechanics to biological function, I review current knowledge on the mechanobiology of selected muscle and cell adhesion proteins including titin, talin, and bacterial pilins. Finally, I discuss emerging methods to modulate protein nanomechanics in living matter, for instance by inducing specific mechanical loss-of-function (mLOF). By interrogating biological systems in a causative manner, these new tools can contribute to further place protein nanomechanics in a biological context.

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“…As reviewed here and elsewhere, the energy landscape of proteins and receptor/ligand bonds is rough, with a hierarchy of substates that are transiently and dynamically visited, substates that can now be directly explored on single molecules using HS-FS at µs-temporal resolution. Future experiments would allow us to determine if this dynamic equilibrium is coloured by dynamic disorder and heterogeneity [132,133]. It may also allow the detection of fast, transient folded states in IDPs or monitor the complete process of protein folding, where short-lived frustration events may occur, and glassy dynamics may dominate [134].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Biological physics by high-speed atomic force microscopy

Casuso

Redondo-Morata

Rico

2020

Phil. Trans. R. Soc. A.

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While many fields have contributed to biological physics, nanotechnology offers a new scale of observation. High-speed atomic force microscopy (HS-AFM) provides nanometre structural information and dynamics with subsecond resolution of biological systems. Moreover, HS-AFM allows us to measure piconewton forces within microseconds giving access to unexplored, fast biophysical processes. Thus, HS-AFM provides a tool to nourish biological physics through the observation of emergent physical phenomena in biological systems. In this review, we present an overview of the contribution of HS-AFM, both in imaging and force spectroscopy modes, to the field of biological physics. We focus on examples in which HS-AFM observations on membrane remodelling, molecular motors or the unfolding of proteins have stimulated the development of novel theories or the emergence of new concepts. We finally provide expected applications and developments of HS-AFM that we believe will continue contributing to our understanding of nature, by serving to the dialogue between biology and physics. This article is part of a discussion meeting issue ‘Dynamic in situ microscopy relating structure and function’.

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Dynamic disorder can explain non-exponential kinetics of fast protein mechanical unfolding

Cited by 10 publications

References 36 publications

Accessibility explains preferred thiol-disulfide isomerization in a protein domain

Accessibility explains preferred thiol-disulfide isomerization in a protein domain

Protein nanomechanics in biological context

Biological physics by high-speed atomic force microscopy

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