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Phase behavior of intrinsically disordered proteins and implications for specificity in DNA binding

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Intrinsically disordered proteins (IDPs) adopt heterogeneous ensembles of conformations under physiological conditions. This talk will present a report on our progress toward understanding the relationship between amino acid sequence and conformational ensembles of IDPs to clarify the role of disorder in physiological function. Using a combination of polymer physics theories, atomistic simulations, and fluorescence-based experiments we have quantified the preference of archetypal IDP sequences for globules versus coils. We have shown that polar tracts, which are sequences that are devoid of canonical hydrophobic residues, can form compact albeit heterogeneous distributions of globules and that the net charge per residue is a useful order parameter that separates coil-forming sequences from those that form globules. This has yielded a predictive phase diagram that is guiding further studies regarding the phase behavior of IDPs.

We have also made progress toward understanding the functional implications of disorder in DNA binding / transcription. In the second half of this talk, I will also provide a report on basic region leucine zippers (bZIPs), which are archetypal transcription factors that form 2:1 complexes with their cognate DNA . Through a combination of atomistic simulations and circular dichroism studies we have characterized the unbound, monomeric ensembles for these proteins. This effort has yielded mechanistic insights regarding the role of disorder in facilitating the oft-quoted advantage of IDPs in molecular recognition namely, achieving a high degree of specificity with low overall affinity.

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