A physical picture for mechanical dissociation of biological complexes: from forces to free energies

Tapia‐Rojo, Rafael; Marcuello, Carlos; Lostao, Anabel; Gómez‐Moreno, Carlos; Mazo, J. J.; Falo, Fernando

doi:10.1039/c6cp07508h

Cited by 11 publications

(9 citation statements)

References 53 publications

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“…Since the advent of force spectroscopy techniques, free energy quantities extracted from pulling experiments have been usually contrasted with those extracted from bulk experiments, such as chemical or thermal denaturation 3,22,[41][42][43] . This comparison implicitly assumes a simple two-state one-dimensional folding landscape, which, while can be reasonable for some systems over a certain scale, should not be generalized.…”

Section: Discussionmentioning

confidence: 99%

Thermal versus mechanical unfolding in a model protein

Tapia‐Rojo

Mazo

Falo

2019

The Journal of Chemical Physics

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Force spectroscopy techniques are often used to learn about the free energy landscape of single biomolecules, typically by recovering free energy quantities that, extrapolated to zero force, are compared to those measured in bulk experiments. However, it is not always clear how the information obtained from a mechanically perturbed system can be related to that obtained using other denaturants, since tensioned molecules unfold and refold along a reaction coordinate imposed by the force, which is unlikely meaningful in its absence.Here, we explore this dichotomy by investigating the unfolding landscape of a model protein, which is first unfolded mechanically through typical force spectroscopy-like protocols, and next thermally. When unfolded by non-equilibrium force extension and constant force protocols, we recover a simple two-barrier landscape, as the protein reaches the extended conformation through a metastable intermediate. Interestingly, foldingunfolding equilibrium simulations at low forces suggested a totally different scenario, where this metastable state plays little role in the unfolding mechanism, and the protein unfolds through two competing pathways 27 . Finally, we use Markov state models to describe the configurational space of the unperturbed protein close to the critical temperature. The thermal dynamics is well understood by a one-dimensional landscape along an appropriate reaction coordinate, however very different from the mechanical picture. In this sense, in our protein model the mechanical and thermal descriptions provide incompatible views of the folding/unfolding landscape of the system, and the estimated quantities to zero force result hard to interpret..

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Section: Discussionmentioning

confidence: 99%

Thermal versus mechanical unfolding in a model protein

Tapia‐Rojo

Mazo

Falo

2019

The Journal of Chemical Physics

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“…The most straightforward way is to estimate the single average of an observable More advanced methods can be used as the jackknife, used in Refs. [46][47][48], or the bootstrap, used in Refs. [19][20][21][22]49], to estimate the error bar.…”

Section: Estimating Error Barsmentioning

confidence: 99%

“…More advanced methods can be used as the jackknife, used in Refs. [46][47][48], or the bootstrap, used in Refs. [19][20][21][22]49], to estimate the error bar.…”

Section: Correcting Blurring Effectmentioning

confidence: 99%

Statistical physics and mesoscopic modeling to interpret tethered particle motion experiments

Manghi

Destainville

Brunet

2019

Methods

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Tethered particle motion experiments are versatile single-molecule techniques enabling one to address in vitro the molecular properties of DNA and its interactions with various partners involved in genetic regulations. These techniques provide raw data such as the tracked particle amplitude of movement, from which relevant information about DNA conformations or states must be recovered. Solving this inverse problem appeals to specific theoretical tools that have been designed in the two last decades, together with the data pre-processing procedures that ought to be implemented to avoid biases inherent to these experimental techniques. These statistical tools and models are reviewed in this paper.

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“…The pore has a square section of width LH and its length is LM , with the same repulsive walls as the whole membrane. The polymer is pulled through the pore with a force driven at constant velocity v. order to induce conformational changes -such as the unfolding of proteins [38], nucleic acids [39], DNA secondary structures as the G-quadruplex [40] -or drive the dissociation of ligand-receptor complexes [41][42][43][44][45]. The same velocity dependent end-pulling has been also implemented in some DNA translocation experiments [46][47][48].…”

Section: Introductionmentioning

confidence: 99%

“…order to induce conformational changes -such as the unfolding of proteins [38], nucleic acids [39], DNA secondary structures as the G-quadruplex [40] -or drive the dissociation of ligand-receptor complexes [41][42][43][44][45]. The same velocity dependent end-pulling has been also implemented in some DNA translocation experiments [46][47][48].…”

Section: Introductionmentioning

confidence: 99%

Force spectroscopy analysis in polymer translocation

Fiasconaro

Falo

2018

Phys. Rev. E

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This paper reports the force spectroscopy analysis of a polymer that translocates from one side of a membrane to the other side through an extended pore, pulled by a cantilever that moves with constant velocity against the damping and the potential barrier generated by the reaction of the membrane walls. The polymer is modeled as a beads-springs chain with both excluded volume and bending contributions, and moves in a stochastic three dimensional environment described by a Langevin dynamics at fixed temperature. The force trajectories recorded at different velocities reveal two exponential regimes: the force increases when the first part of the chain enters the pore, and then decreases when the first monomer reaches the trans region. The spectroscopy analysis of the force values permit the estimation of the limit force to allow the translocation, related to the free energy barrier. The stall force to maintain the polymer fixed has been also calculated independently, and its value confirms the force spectroscopy outcomes.

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A physical picture for mechanical dissociation of biological complexes: from forces to free energies

Cited by 11 publications

References 53 publications

Thermal versus mechanical unfolding in a model protein

Thermal versus mechanical unfolding in a model protein

Statistical physics and mesoscopic modeling to interpret tethered particle motion experiments

Force spectroscopy analysis in polymer translocation

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