Unexpected mechanochemical complexity in the mechanistic scenarios of disulfide bond reduction in alkaline solution

Abstract

The reduction of disulfides has a broad importance in chemistry, biochemistry and materials science, particularly those methods that use mechanochemical activation. Here we show, using isotensional simulations, that strikingly different mechanisms govern disulfide cleavage depending on the external force. Desolvation and resolvation processes are found to be crucial, as they have a direct impact on activation free energies. The preferred pathway at moderate forces, a bimolecular SN2 attack of OH at sulfur, competes with unimolecular C–S bond rupture at about 2 nN, and the latter even becomes barrierless at greater applied forces. Moreover, our study unveils a surprisingly rich reactivity scenario that also includes the transformation of concerted SN2 reactions into pure bond-breaking processes at specific forces. Given that these forces are easily reached in experiments, these insights will fundamentally change our understanding of mechanochemical activation in general, which is now expected to be considerably more intricate than previously thought.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Force dependence of the computed activation free energy, , for all five depicted reaction pathways.
Figure 2: Solvation of the OH nucleophile by water studied as a function of external force using the rigorous all-QM AIMD approach and a QM/MM hybrid MD approximation.
Figure 3: Change of the reaction mechanism from a concerted one-step reaction to a two-step process for the OH attack at an α-carbon.
Figure 4: Change of the α-elimination reaction mechanism with applied force.

References

  1. 1

    Beyer, M. K. & Clausen-Schaumann, H. Mechanochemistry: the mechanical activation of covalent bonds. Chem. Rev. 105, 2921–2948 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Caruso, M. M. et al. Mechanically-induced chemical changes in polymeric materials. Chem. Rev. 109, 5755–5798 (2009).

    CAS  Article  Google Scholar 

  3. 3

    Black, A. L., Lenhardt, J. M. & Craig, S. L. From molecular mechanochemistry to stress-responsive materials. J. Mater. Chem. 21, 1655–1663 (2011).

    Article  CAS  Google Scholar 

  4. 4

    Huang, Z. & Boulatov, R. Chemomechanics: chemical kinetics for multiscale phenomena. Chem. Soc. Rev. 40, 2359–2384 (2011).

    Article  CAS  Google Scholar 

  5. 5

    Ribas-Arino, J. & Marx, D. Covalent mechanochemistry: theoretical concepts and computational tools with applications to molecular nanomechanics. Chem. Rev. 112, 5412–5487 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Wiita, A. P., Ainavarapu, S. R. K., Huang, H. H. & Fernandez, J. M. Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniques. Proc. Natl Acad. Sci. USA 103, 7222–7227 (2006).

    Article  CAS  Google Scholar 

  7. 7

    Wiita, A. P. et al. Probing the chemistry of thioredoxin catalysis with force. Nature 450, 124–127 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Ainavarapu, S. R. K., Wiita, A. P., Dougan, L., Uggerud, E. & Fernandez, J. M. Single-molecule force spectroscopy measurements of bond elongation during a bimolecular reaction. J. Am. Chem. Soc. 130, 6479–6487 (2008).

    Article  CAS  Google Scholar 

  9. 9

    Liang, J. & Fernandez, J. M. Mechanochemistry: one bond at a time. ACS Nano 3, 1628–1645 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Garcia-Manyes, S., Liang, J., Szoszkiewicz, R., Kuo, T. L. & Fernandez, J. M. Force-activated reactivity switch in a bimolecular chemical reaction. Nat. Chem. 1, 236–242 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Alegre-Cebollada, J., Kosuri, P., Rivas-Pardo, J. A. & Fernandez, J. M. Direct observation of disulfide isomerization in a single protein. Nat. Chem. 3, 882–887 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Garcia-Manyes, S., Kuo, T.-L. & Fernandez, J. M. Contrasting the individual reactive pathways in protein unfolding and disulfide bond reduction observed within a single protein. J. Am. Chem. Soc. 133, 3104–3113 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Liang, J. & Fernández, J. M. Kinetic measurements on single-molecule disulfide bond cleavage. J. Am. Chem. Soc. 133, 3528–3534 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Popa, I., Kosuri, P., Alegre-Cebollada, J., Garcia-Manyes, S. & Fernandez, J. M. Force dependency of biochemical reactions measured by single-molecule force-clamp spectroscopy. Nat. Protocols 8, 1261–1276 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Szoszkiewicz, R . Single-molecule studies of disulfide bond reduction pathways used by human thioredoxin. Biophys. Chem. 173–174, 31–38 (2013).

    Article  CAS  Google Scholar 

  16. 16

    Kucharski, T. J. et al. Kinetics of thiol/disulfide exchange correlate weakly with the restoring force in the disulfide moiety. Angew. Chem. Int. Ed. 48, 7040–7043 (2009).

    Article  CAS  Google Scholar 

  17. 17

    Tian, Y., Kucharski, T. J., Yang, Q. Z. & Boulatov, R . Model studies of force-dependent kinetics of multi-barrier reactions. Nat. Commun. 4, 2538 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Hofbauer, F. & Frank, I. Disulfide bond cleavage: a redox reaction without electron transfer. Chem. Eur. J. 16, 5097–5101 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Li, W. & Gräter, F. Atomistic evidence of how force dynamically regulates thiol/disulfide exchange. J. Am. Chem. Soc. 132, 16790–16795 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Iozzi, M. F., Helgaker, T. & Uggerud, E. Influence of external force on properties and reactivity of disulfide bonds. J. Phys. Chem. A 115, 2308–2315 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Baldus, I. B. & Gräter, F. Mechanical force can fine-tune redox potentials of disulfide bonds. Biophys. J. 102, 622–629 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Keten, S., Chou, C.-C., van Duin, A. C. T. & Buehler, M. J. Tunable nanomechanics of protein disulfide bonds in redox microenvironments. J. Mech. Behav. Biomed. Mater. 5, 32–40 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Hofbauer, F. & Frank, I. CPMD simulation of a bimolecular chemical reaction: nucleophilic attack of a disulfide bond under mechanical stress. Chem. Eur. J. 18, 16332–16338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Dopieralski, P. et al. The Janus-faced role of external forces in mechanochemical disulfide bond cleavage. Nat. Chem. 5, 685–691 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Anjukandi, P., Dopieralski, P., Ribas-Arino, J . & Marx, D. The effect of tensile stress on the conformational free energy landscape of disulfide bonds. PLoS ONE 9, e108812 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Zhou, B., Baldus, I. B., Li, W., Edwards, S. A. & Gräter, F. Identification of allosteric disulfides from prestress analysis. Biophys. J. 107, 672–681 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Wouters, M. A., Fan, S. W. & Haworth, N. L. Disulfides as redox switches: from molecular mechanisms to functional significance. Antioxid. Redox Signal. 12, 53–91 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Matthias, L. J. et al. Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1. Nat. Immunol. 3, 727–732 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Hogg, P. J. Disulfide bonds as switches for protein function. Trends Biochem. Sci. 28, 210–214 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Ahamed, J. et al. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc. Natl Acad. Sci. USA 103, 13932–13937 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Schmidt, B., Ho, L. & Hogg, P. J. Allosteric disulfide bonds. Biochemistry 45, 7429–7433 (2006).

    Article  CAS  Google Scholar 

  32. 32

    Guo, X., Xiang, D., Duan, G. & Mou, P. A review of mechanochemistry applications in waste management. Waste Manag. 30, 4–10 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Zhang, X., Lu, Z., Tian, D., Li, H. & Lu, C. Mechanochemical devulcanization of ground tire rubber and its application in acoustic absorbent polyurethane foamed composites. J. Appl. Polym. Sci. 127, 4006–4014 (2013).

    Article  CAS  Google Scholar 

  34. 34

    Rust, H. Non-chemical, mechanical procedure for the devulcanization of scrap rubber and/or elastomers and apparatus therefor. US patent 8,957,119 (2015).

  35. 35

    Mars, W. V. & Fatemi, A. Factors that affect the fatigue life of rubber: a literature survey. Rubber Chem. Technol. 77, 391–412 (2004).

    Article  CAS  Google Scholar 

  36. 36

    Persson, B. N. J., Albohr, O., Heinrich, G. & Ueba, H. Crack propagation in rubber-like materials. J. Phys. Condens. Matter 17, R1071–R1142 (2005).

    Article  CAS  Google Scholar 

  37. 37

    Barcan, G. A., Zhang, X. & Waymouth, R. Structurally dynamic hydrogels derived from 1,2-dithiolanes. J. Am. Chem. Soc. 137, 5650–5653 (2015).

    Article  CAS  Google Scholar 

  38. 38

    An, S. Y., Arunbabu, D., Noh, S. M., Song, Y. K. & Oh, J. K. Recent strategies to develop self-healable crosslinked polymeric networks. Chem. Commun. 51, 13058–13070 (2015).

    Article  CAS  Google Scholar 

  39. 39

    Marx, D. & Hutter, J. Ab Initio Molecular Dynamics: Basic Theory and Advanced Methods (Cambridge Univ. Press, 2009).

    Google Scholar 

  40. 40

    Krupička, M. & Marx, D. Disfavoring mechanochemical reactions by stress-induced steric hindrance. J. Chem. Theory Comput. 11, 841–846 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Parker, A. J. & Kharasch, N. The scission of the sulfur–sulfur bond. Chem. Rev. 59, 583–628 (1959).

    Article  CAS  Google Scholar 

  42. 42

    Singh, R. & Whitesides, G. M. in Supplement S: The Chemistry of Sulphur-Containing Functional Groups (eds Patai, S. & Rappoport, Z.) 633–658 (Wiley, 1993).

    Google Scholar 

  43. 43

    Hayes, J. M. & Bachrach, S. M. Effect of micro and bulk solvation on the mechanism of nucleophilic substitution at sulfur in disulfides. J. Phys. Chem. A 107, 7952–7961 (2003).

    Article  CAS  Google Scholar 

  44. 44

    Fernandes, P. A. & Ramos, M. J. Theoretical insights into the mechanism for thiol/disulfide exchange. Chem. Eur. J. 10, 257–266 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Bach, R. D., Dmitrenko, O. & Thorpe, C. Mechanism of thiolate–disulfide interchange reactions in biochemistry. J. Org. Chem. 73, 12–21 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Swan, J. M. Mechanism of alkaline degradation of cystine residues in protein. Nature 179, 965 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Cecil, R. & McPhee, J. R. The sulfur chemistry of proteins. Adv. Protein Chem. 14, 255–389 (1959).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Florence, T. M. Degradation of protein disulphide bonds in dilute alkali. Biochem. J. 189, 507–520 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Grabowski, J. J. & Zhang, L. Dimethyl disulfide: anion–molecule reactions in the gas phase at 300 K. J. Am. Chem. Soc. 111, 1193–1203 (1989).

    Article  CAS  Google Scholar 

  50. 50

    Bachrach, S. M. & Pereverzev, A. Competing elimination and substitution reactions of simple acyclic disulfides. Org. Biomol. Chem. 3, 2095–2101 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Tarbell, D. S. & Harnish, D. Cleavage of the carbon–sulfur bond in divalent sulfur compounds. Chem. Rev. 49, 1–90 (1951).

    Article  CAS  Google Scholar 

  52. 52

    Paranjothy, M., Siebert, M. R., Hase, W. L. & Bachrach, S. M. Mechanism of thiolate–disulfide exchange: addition−elimination or effectively SN2? Effect of a shallow intermediate in gas-phase direct dynamics simulations. J. Phys. Chem. A 116, 11492–11499 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Heverly-Coulson, G. S., Boyd, R. J., Mó, O. & Yáñez, M. Revealing unexpected mechanisms for nucleophilic attack on S–S and Se–Se bridges. Chem. Eur. J. 19, 3629–3638 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Ribas-Arino, J., Shiga, M. & Marx, D. Understanding covalent mechanochemistry. Angew. Chem. Int. Ed. 48, 4190–4193 (2009).

    Article  CAS  Google Scholar 

  55. 55

    Dopieralski, P., Ribas-Arino, J. & Marx, D. Force-transformed free energy surfaces and trajectory shooting simulations reveal the mechano-stereochemistry of cyclopropane ring-opening reactions. Angew. Chem. Int. Ed. 50, 7105–7108 (2011).

    Article  CAS  Google Scholar 

  56. 56

    Marx, D., Chandra, A. & Tuckerman, M. E. Aqueous basic solutions: hydroxide solvation, structural diffusion, and comparison to the hydrated proton. Chem. Rev. 110, 2174–2216 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Bachrach, S. M. Computational Organic Chemistry (Wiley, 2007).

    Google Scholar 

  58. 58

    Mohamed, A. A. & Jensen, F. Steric effects in SN2 reactions. The influence of microsolvation. J. Phys. Chem. A 105, 3259–3268 (2001).

    Article  CAS  Google Scholar 

  59. 59

    Dopieralski, P., Ribas-Arino, J., Anjukandi, P., Krupicka, M. & Marx, D. Force–induced reversal of β-eliminations: stressed disulfide bonds in alkaline solution. Angew. Chem. Int. Ed. 55, 1304–1308 (2016).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Deutsche Forschungsgemeinsschaft (Reinhart Koselleck Grant ‘Understanding Mechanochemistry’ MA 1547/9 and Cluster of Excellence ‘RESOLV’ EXC 1069), Alexander von Humboldt Stiftung (Humboldt Fellowships to J.R.A), Spanish Government (Ramón y Cajal Fellowship to J.R.A.), National Science Center Poland under Grant No. 2014/13/B/ST4/05009 and Ministry of Science and Higher Education Poland under Grant No. 627/STYP/9/20l4 (Fellowships to P.D.) for partial financial support. The authors acknowledge the Gauss Centre for Supercomputing (GCS) for providing computing time for a GCS Large Scale Project on JUQUEEN at the Jülich Supercomputing Centre as well as additional computational support by BOVILAB@RUB, HPC–RESOLV, Rechnerverbund–NRW, Wrocław Supercomputer Center, Galera–ACTION Cluster and Academic Computer Center in Gdańsk (CI TASK).

Author information

Affiliations

Authors

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; P.D., J.R.-A. and D.M. co-wrote the paper.

Corresponding authors

Correspondence to Przemyslaw Dopieralski or Jordi Ribas–Arino.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 4308 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dopieralski, P., Ribas–Arino, J., Anjukandi, P. et al. Unexpected mechanochemical complexity in the mechanistic scenarios of disulfide bond reduction in alkaline solution. Nature Chem 9, 164–170 (2017). https://doi.org/10.1038/nchem.2632

Download citation

Further reading