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The Flory isolated pair hypothesis (IPH) is one of the corner stones of the random coil model, which is generally invoked to describe the conformational dynamics of unfolded and intrinsically disordered proteins (IDPs). It stipulates, that individual residues sample the entire sterically allowed space of the Ramachandran plot without exhibiting any correlations with the conformational dynamics of its neighbors. However, multiple lines of computational, bioinformatic and experimental evidence suggest that nearest neighbors have a significant influence on the conformational sampling of amino acid residues. This implies that the conformational entropy of unfolded polypeptides and proteins is much less than one would expect based on the Ramachandran plots of individual residues. A further implication is that the Gibbs energies of residues in unfolded proteins or polypeptides are not additive. This review provides an overview of what is currently known and what has yet to be explored regarding nearest neighbor interactions in unfolded proteins.
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The relevance of short peptides for an understanding of unfolded and intrinsically disordered proteins
Over the last thirty years the unfolded state of proteins has attracted considerable interest owing to the discovery of intrinsically disordered proteins which perform a plethora of functions despite resembling unfolded proteins to a significant extent. Research on both, unfolded and disordered proteins has revealed that their conformational properties can deviate locally from random coil behavior. In this context results from work on short oligopeptides suggest that individual amino acid residues sample the sterically allowed fraction of the Ramachandran plot to a different extent. Alanine has been found to exhibit a peculiarity in that it has a very high propensity for adopting polyproline II like conformations. This Perspectives article reviews work on short peptides aimed at exploring the Ramachandran distributions of amino acid residues in different contexts with experimental and computational means. Based on the thus provided overview the article discussed to what extent short peptides can serve as tools for exploring unfolded and disordered proteins and as benchmarks for the development of a molecular dynamics force field.
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- Award ID(s):
- 1817650
- PAR ID:
- 10438270
- Date Published:
- Journal Name:
- Physical Chemistry Chemical Physics
- Volume:
- 25
- Issue:
- 17
- ISSN:
- 1463-9076
- Page Range / eLocation ID:
- 11908 to 11933
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d3cp00483j
