Looking at quickly the two papers are talking about dynamics on very different time-scales. The Tompa book refers to the dynamics of local (residue level not domian level) segmental motions and the formation of transient structural elements on the ns time scale. The Fang paper is using HEx as a measure of solvent exposure. This measures local unfolding on the sec -minute time-scale and is less a measure of functional dynamics as most people think about it then a measure of protein stability. Looking at quickly, the statement that 3° structure does not to correlate with protein dynamics is not justified by their data (looking at the wrong time-scale). Also note segmental motion that does not result in a change in H-bonding pattern will not be detected by their technique (solvent exposure of the amide backbone is the same).

Ahh I see.. thought the method's validity to conclusions would've been checked at peer review but there we go. Thanks for clarification. Yes, same amount of solvent wrapping, could be. Thanks Jeffrey

A limit in the understanding of biological functions in which IDPs are involved, it is often the lack of knowledge of the physical basis on which these functions rely (the molecular mechanism). Recent data, obtained borrowing concepts from polymer physics and the physics of spin glasses, consider IDPs as polyelectrolytes, as well as they are showing that this approach is much closer to their physical reality. In the literature there are a lot of interesting papers that in the last years have studied this problem but, surprisingly, they are not so cited as they should. See for example the papers of Pappu’s group. The structural interpretation of the IDP functional roles was always associated with two main structural properties, be extended, or in any case swollen, and consequently be structurally flexible. This view is strongly reinforced by the limited presence of hydrophobic residues that does not allow the formation of a compact core. This way of thinking is essentially derived from a globular-centric vision. In fact, the structural characteristics of IDPs are borrowed from the knowledge of globular proteins. When we deal with complex macromolecular problems, we go back to simpler model systems, whose properties are then transferred to the complex models. In recent years, numerous articles have been published concerning studies of the structural properties possessed by model compounds of IDPs. The picture that comes out leads to think that IDPs are charged organic polymers, or strong polyampholytes, and have to be treated with the laws of polymer physics. In this context, their net charge assumes a fundamental importance in determining conformation and shape, and, what is rather unusual for globular proteins, the water is often a poor solvent for IDPs and for this reason sometimes they collapse as globules, although they are polar and charged. Moreover, they do not tend to a single native structure as globular proteins do, but rather are represented as an ensemble of conformers at equilibrium with a wide distribution of different molecular shapes. The conformation of the IDP ensembles is influenced by the distribution of charges on the protein segment. Rahul and Pappu by means of a large-scale simulation of different IDPs from DisProt database were able to build a Diagram of state for IDPs were the different regions represent a continuum of possibilities between the type of conformations expected to be sampled by IDP. Thus, the word globule does not mean native globular structure with some secondary/tertiary structure topologically fixed in time but rather a collapsed globule with an ensemble of conformations that fail to fold autonomously into singular structures. Therefore, this is the main road to study the physical state of these proteins which are disclosing their structure as strong polyampholytes by means of the physics of charged organic polymers.

I agree about the lack of mention of ampholytes - Oldfield and Dunker (2014) "IDPs and IDPRs" in Annu. Rev. Biochem. (link at bottom of this post) seemed to me quite 'up to date' (bringing up some IDP functions other reviews miss), and discusses the polyampholyte work as do:

• Uversky (2013) A decade and a half of protein intrinsic disorder - biology still waits for physics.

⇢ citing Mao (2010) Net charge per residue modulates conformational ensembles of IDPs. PNAS 107:8183-8188

• Mao (2012) Describing sequence-ensemble relationships for intrinsically disordered proteins

⇢ citing Dobrynin (2004) Polyampholytes. J. Polym. Sci. B. 42, 3513–3538

• Schuler (2013) Single-molecule spectroscopy of protein folding dynamics--expanding scope and timescales

⇢ citing Muller-Spath (2010) Charge interactions can dominate the dimensions of intrinsically disordered proteins. PNAS, 107:14609-14614,

⇢ & Hofmann (2008) Coulomb forces control the density of the collapsed unfolded state of barstar. J Mol Biol, 376:597-605.

Thank you for taking the time for such a long answer Giovanni! Just thought I'd hunt these down from my library in case anyone reading this is wondering what relevant works you think aren't being cited enough.

This discussion seems to have shifted somewhat though, and I suppose it might be a good idea for further comments to be about 2° / 3° dynamics correlation as per the original question, just for the sake of not giving the question's followers a ton of unrelated notifications :–) Unless you were trying to draw my attention to something there, in which case please let me know!

http://www.annualreviews.org/doi/abs/10.1146/annurev-biochem-072711-164947?journalCode=biochem