Small-molecule binding to intrinsically disordered proteins

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• Dr Gabi Heller, Newnham College, Cambridge
• Monday 07 November 2022, 14:00-14:30
• Dept of Chemistry, Wolfson Lecture Theatre .

If you have a question about this talk, please contact Jerelle Joseph.

Intrinsically disordered proteins are highly prevalent biomolecules (totalling 30-40% of human proteins) that rapidly interconvert between conformations. Unlike structured proteins, whose behaviours are well-described by single three-dimensional structures, disordered proteins are best characterized by dynamic ensembles of interconverting conformations. Their peculiar, dynamic nature enables them to act as network hubs in crucial biological processes. Dysregulation of these proteins is therefore implicated in many diseases, including cancer, cardiovascular disease, type II diabetes, and neurodegeneration. Despite their importance, the characterization of the structures, functions, and pathological roles of disordered proteins is an enormous challenge. In my talk, I will describe integrative methods, combining molecular dynamics simulations with experimental data from nuclear magnetic resonance spectroscopy to characterise the pathogenicity and druggability of disordered proteins. My talk will highlight our recent work on the monomeric form of the amyloid-β peptide, whose aggregation is a hallmark of Alzheimer’s disease. In particular, I will focus on the identification and characterization of a small, drug-like molecule that sequesters amyloid-β in its soluble monomeric form and prevents its toxic aggregation. Using all-atom molecular dynamics simulations and biophysical experiment, we observe the binding interaction to be extremely dynamic, such that amyloid-β not only remains disordered in the bound form, but also increases its conformational entropy. A detailed understanding of the binding mechanisms between small molecules and disordered proteins may lead to the ability to engineer improved interactions, yielding drugs targeting these proteins that are highly prevalent in many human diseases.

This talk is part of the Lennard-Jones Centre series.

This talk is included in these lists:

• Dept of Chemistry, Wolfson Lecture Theatre
• Hanchen DaDaDash
• Lennard-Jones Centre

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