Intrinsically Disordered Energy Landscapes
Chebaro, Yassmine C
Ballard, Andrew J
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Chebaro, Y. C., Ballard, A. J., Chakraborty, D., & Wales, D. (2015). Intrinsically Disordered Energy Landscapes. Scientific Reports, 5 (10386)https://doi.org/10.1038/srep10386
Analysis of an intrinsically disordered protein (IDP) reveals an underlying multifunnel structure for the energy landscape. We suggest that such ‘intrinsically disordered’ landscapes, with a number of very different competing low-energy structures, are likely to characterise IDPs, and provide a useful way to address their properties. In particular, IDPs are present in many cellular protein interaction networks, and several questions arise regarding how they bind to partners. Are conformations resembling the bound structure selected for binding, or does further folding occur on binding the partner in a induced-fit fashion? We focus on the p53 upregulated modulator of apoptosis (PUMA) protein, which adopts an -helical conformation when bound to its partner, and is involved in the activation of apoptosis. Recent experimental evidence shows that folding is not necessary for binding, and supports an induced-fit mechanism. Using a variety of computational approaches we deduce the molecular mechanism behind the instability of the PUMA peptide as a helix in isolation. We find significant barriers between partially folded states and the helix. Our results show that the favoured conformations are molten-globule like, stabilised by charged and hydrophobic contacts, with structures resembling the bound state relatively unpopulated in equilibrium.
Computational biology and bioinformatics, Theoretical chemistry
The authors thank Prof. Jane Clarke, Dr. Chris Whittleston, Dr. Joanne Carr, Dr. Iskra Staneva and Dr. David de Sancho for helpful discussions. Y.C. and A.J.B. acknowledge funding from the EPSRC grant number EP/I001352/1, D.C. gratefully acknowledges the Cambridge Commonwealth European and International Trust for financial support and D.J.W. the ERC for an Advanced Grant.
External DOI: https://doi.org/10.1038/srep10386
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248139
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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