At this year’s Annual Meeting, the Intrinsically Disordered Proteins (IDP) Subgroup celebrated five Student Research Achievement Award (SRAA) winners:
William (Austin) Elam, Hilser Group, Johns Hopkins University, characterized the prevalence of the polyproline II (PII) conformation in denatured ensembles using spectroscopic, calorimetric, and computational approaches. Specifically, the energetics of SH3 binding to a family of SosY peptides (measured with isothermal titration calorimetry) was used to quantify the PII propensity, for all 20 amino acids. A sequence-based predictor was developed to estimate the PII propensities. One conclusion of this study is that IDPs are enriched in PIIpromoting sequence features. This work sheds light on the conformational properties of the denatured state in general and IDPs in particular, confirming that disordered states can have unique conformational tendencies.
Albert Mao, Pappu Group, Washington University, evaluated how the net charge per residue modulates the extent of globular collapse using the ABSINTH implicit solvation model. As expected, regions having a low net charge per residue were found to have a collapsed globular conformational ensemble. Highly anionic regions, however, had unexpectedly large amounts of collapse, possibly due to the treatment of counter-ions in the solvation model. Mao also introduced a quantity called the “mixing extent,” which, for an input sequence, quantifies the fraction of permuted sequences having fewer adjacent pairs of distinct characters. Mixing extent did not correlate with alpha-helical or beta-strand propensity. Mao is continuing to correlate the mixing extent with conformational properties towards improving our understanding of sequence-structure relationships and IDP ensembles.
Elizabeth Middleton, Rhoades Group, Yale University, presented her work studying the interactions between α-synuclein (αS), an intrinsically disordered Parkinson’s disease protein, and Hsp70, which moderates αS toxicity. Using fluorescence correlation spectroscopy (FCS) and fl uorescence anisotropy, Hsp70 does not appear to interact with the unstructured monomeric αS. However, Hsp70 does bind to the structured forms of αS and inhibits both membrane association and aggregation of αS. Middleton’s recent work suggests that Hsp70 may maintain αS in a nontoxic state. Elizabeth intends on using FRET to further probe structural changes that occur upon αS interaction with Hsp70 and explore the eff ects the pathological mutations of αS on this interaction.
Natasha Pirman, Fanucci Group, University of Florida, has investigated the mobility and conformational changes of IDPs using a multifrequency approach to site-directed spin-labeling electron paramagnetic resonance (SDSLEPR) spectroscopy. Pirman has monitored the induced unstructured-to-α-helical transition of IA3, a 68 residue IDP, upon addition of 2,2,2-trifl uoroethanol (TFE) at both the X- and W-band frequencies. X-band EPR spectral line shapes support a two-state model and further analysis can provide site-specific information on a residue level while W-band data analysis reveals more site-specifi c structural changes. Pirman’s work has shown that multi-frequency EPR can provide insight into structural changes occurring in IDP systems that are otherwise difficult to characterize.
Davit Potoyan, Papoian Lab, University of Maryland, College Park, presented his work on the highly flexible N- and C-terminal protrusions of histone proteins called histone tails. These regions facilitate the compaction of DNA to chromatin and act as biomolecular switches regulating various genetic processes. Potoyan has used all atom replica exchange molecular dynamics (REMD) to probe the intrinsic conformational preferences of four histone tails, H4, H3, H2B, and H2A. The free energy landscape generated from his simulations demonstrated that most tails contain specifi c fl ickering secondary structural elements. Currently, Potoyan is studying the DNA binding of histone tails and how covalent modifi cations infl uence the binding affinity in order to explain certain aspects of their functional behavior.
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—Ryan Hoffman and Lisette Fred, IDP Council Members
June 2011 Table of Contents