@article {2018|2132,
	title = {The force-dependent mechanism of DnaK-mediated mechanical folding},
	journal = {Sci Adv},
	volume = {4},
	year = {2018},
	month = {Feb},
	pages = {eaaq0243},
	abstract = {<p>It is well established that chaperones modulate the protein folding free-energy landscape. However, the molecular determinants underlying chaperone-mediated mechanical folding remain largely elusive, primarily because the force-extended unfolded conformation fundamentally differs from that characterized in biochemistry experiments. We use single-molecule force-clamp spectroscopy, combined with molecular dynamics simulations, to study the effect that the Hsp70 system has on the mechanical folding of three mechanically stiff model proteins. Our results demonstrate that, when working independently, DnaJ (Hsp40) and DnaK (Hsp70) work as holdases, blocking refolding by binding to distinct substrate conformations. Whereas DnaK binds to molten globule-like forms, DnaJ recognizes a cryptic sequence in the extended state in an unanticipated force-dependent manner. By contrast, the synergetic coupling of the Hsp70 system exhibits a marked foldase behavior. Our results offer unprecedented molecular and kinetic insights into the mechanisms by which mechanical force finely regulates chaperone binding, directly affecting protein elasticity.</p>
},
	doi = {10.1126/sciadv.aaq0243},
	author = {Perales-Calvo, Judit and Giganti, David and Guillaume Stirnemann and Garcia-Manyes, Sergi}
}
@article {2018|2136,
	title = {Forcing the reversibility of a mechanochemical reaction},
	journal = {Nat Commun},
	volume = {9},
	year = {2018},
	month = {08},
	pages = {3155},
	abstract = {<p>Mechanical force modifies the free-energy surface of chemical reactions, often enabling thermodynamically unfavoured reaction pathways. Most of our molecular understanding of force-induced reactivity is restricted to the irreversible homolytic scission of covalent bonds and ring-opening in polymer mechanophores. Whether mechanical force can by-pass thermodynamically locked reactivity in heterolytic bimolecular reactions and how this impacts the reaction reversibility remains poorly understood. Using single-molecule force-clamp spectroscopy, here we show that mechanical force promotes the thermodynamically disfavored SN2 cleavage of an individual protein disulfide bond by poor nucleophilic organic thiols. Upon force removal, the transition from the resulting high-energy unstable mixed disulfide product back to the initial, low-energy disulfide bond reactant becomes suddenly spontaneous, rendering the reaction fully reversible. By rationally varying the nucleophilicity of a series of small thiols, we demonstrate how force-regulated chemical kinetics can be finely coupled with thermodynamics to predict and modulate the reversibility of bimolecular mechanochemical reactions.</p>
},
	doi = {10.1038/s41467-018-05115-6},
	author = {Beedle, Amy E M and Mora, Marc and Davis, Colin T and Snijders, Ambrosius P and Guillaume Stirnemann and Garcia-Manyes, Sergi}
}
