Biophysical Reviews

, Volume 5, Issue 2, pp 85–98 | Cite as

The loop hypothesis: contribution of early formed specific non-local interactions to the determination of protein folding pathways

  • Tomer Orevi
  • Gil Rahamim
  • Gershon Hazan
  • Dan Amir
  • Elisha Haas
Review

Abstract

The extremely fast and efficient folding transition (in seconds) of globular proteins led to the search for some unifying principles embedded in the physics of the folding polypeptides. Most of the proposed mechanisms highlight the role of local interactions that stabilize secondary structure elements or a folding nucleus as the starting point of the folding pathways, i.e., a “bottom–up” mechanism. Non-local interactions were assumed either to stabilize the nucleus or lead to the later steps of coalescence of the secondary structure elements. An alternative mechanism was proposed, an “up–down” mechanism in which it was assumed that folding starts with the formation of very few non-local interactions which form closed long loops at the initiation of folding. The possible biological advantage of this mechanism, the “loop hypothesis”, is that the hydrophobic collapse is associated with ordered compactization which reduces the chance for degradation and misfolding. In the present review the experiments, simulations and theoretical consideration that either directly or indirectly support this mechanism are summarized. It is argued that experiments monitoring the time-dependent development of the formation of specifically targeted early-formed sub-domain structural elements, either long loops or secondary structure elements, are necessary. This can be achieved by the time-resolved FRET-based “double kinetics” method in combination with mutational studies. Yet, attempts to improve the time resolution of the folding initiation should be extended down to the sub-microsecond time regime in order to design experiments that would resolve the classes of proteins which first fold by local or non-local interactions.

Keywords

Protein folding Loop hypothesis Hydrophobic collapse Ordered compatization 

Notes

Acknowledgments

We are grateful to Mr. E. Zimerman and D. Freedman for excellent technical assistance and to Eldad Ben Ishay, Eitan Lerner, and Asaf Grupi for their contributions and discussions. This study was supported by grants from the Israel Science Foundation (ISF1464/10); the EU Marie Curie TOK grant (29936), the US-Israel Binational science foundation (BSF 2005270); the Damadian Center for Magnetic Resonance Research, Bar-Ilan University.

Conflict of interest

None.

Supplementary material

12551_2013_113_MOESM1_ESM.docx (40 kb)
ESM 1 (DOCX 39 kb)

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Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Tomer Orevi
    • 1
  • Gil Rahamim
    • 1
  • Gershon Hazan
    • 1
  • Dan Amir
    • 1
  • Elisha Haas
    • 1
  1. 1.The Goodman Faculty of Life SciencesBar Ilan UniversityRamat GanIsrael

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