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The Janus-faced role of external forces in mechanochemical disulfide bond cleavage

Nature Chemistry volume 5, pages 685–691 (2013)Cite this article

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Abstract

Recent force microscopy measurements on the mechanically activated cleavage of a protein disulfide bond through reaction with hydroxide ions revealed that for forces greater than 0.5 nN, the acceleration of the reaction rate is substantially reduced. Here, using ab initio simulations, we trace this ‘reactivity switch’ back to a dual role played by the mechanical force, which leads to antagonistic effects. On the one hand, the force performs work on the system, and thereby accelerates the reaction. On the other hand, the force also induces a conformational distortion that involves the S–S–C–C dihedral angle, which drives the disulfide into a conformation that is shielded against nucleophilic attack because of steric hindrance. The discovery of force-induced conformational changes that steer chemical reactivity provides a new key concept that is expected to be relevant beyond this specific case, for example in understanding how ‘disulfide switches’ regulate protein function and for the rational design of mechanoresponsive materials.

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Figure 1: The computed force dependence of the activation free energy, ΔA‡(F), and reaction rate of disulfide-bond reduction by hydroxide ions features a mechanochemical switch.
Figure 2: The solvation shell of the hydroxide anion nucleophile changes as it approaches the disulfide bridge and reacts with it.
Figure 3: The external force reshapes the FES for the SN2 cleavage of diethyl disulfide by OH−.
Figure 4: The external force has a huge impact on the FEP along the S–S*–C–C dihedral angle of diethyl disulfide, in contrast to that along the C–S–S–C dihedral angle.

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Acknowledgements

We are grateful to the Deutsche Forschungsgemeinsschaft (Reinhart Koselleck Grant Understanding Mechanochemistry (MA 1547/9) and Cluster of Excellence RESOLV (EXC 1069)), Alexander von Humboldt Stiftung (Humboldt Fellowship to J.R-A), the Spanish Government (Ramón y Cajal Fellowship to J.R-A.) and the Research Department Interfacial Systems Chemistry for partial financial support. The authors gratefully acknowledge the Gauss Centre for Supercomputing (GCS) for providing computing time for a GCS Large Scale Project on JUQUEEN at Jülich Supercomputing Centre (JSC) as well as computational support by BOVILAB@RUB, Rechnerverbund-NRW, Wroclaw Supercomputer Center (WCSS), Galera-ACTION Cluster and Academic Computer Center in Gdańsk (CI TASK).

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Author notes

  1. Jordi Ribas-Arino & Janos Kiss

    Present address: Present addresses: Departament de Química Física and IQTCUB, Universitat de Barcelona, Av. Diagonal 645, 08028, Barcelona, Spain (J.R-A.), Max-Planck-Institut für Chemische Physik fester Stoffe, Nöthnitzer Strasse 40, 01187 Dresden, Germany (J.K.),

Authors and Affiliations

  1. Lehrstuhl für Theoretische Chemie, Ruhr-Universität Bochum, Bochum, 44780, Germany

    Przemyslaw Dopieralski, Jordi Ribas-Arino, Padmesh Anjukandi, Martin Krupicka, Janos Kiss & Dominik Marx

  2. Faculty of Chemistry, University of Wroclaw, Joliot-Curie 14, Wroclaw, 50-383, Poland

    Przemyslaw Dopieralski

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Contributions

P.D, J.R-A. and D.M. conceived and designed the research; P.D. performed the calculations; P.D, J.R-A., P.A., M.K. and D.M. analysed the data; J.K. contributed analysis tools; J.R-A., P.D. and D.M. co-wrote the paper.

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Correspondence to Przemyslaw Dopieralski or Jordi Ribas-Arino.

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Dopieralski, P., Ribas-Arino, J., Anjukandi, P. et al. The Janus-faced role of external forces in mechanochemical disulfide bond cleavage. Nature Chem 5, 685–691 (2013). https://doi.org/10.1038/nchem.1676

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