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SUMMARY:Small-molecule binding to intrinsically disordered proteins - Dr G
 abi Heller\, Newnham College\, Cambridge
DTSTART:20221107T140000Z
DTEND:20221107T143000Z
UID:TALK192293@talks.cam.ac.uk
CONTACT:Jerelle Joseph
DESCRIPTION:Intrinsically disordered proteins are highly prevalent biomole
 cules (totalling 30-40% of human proteins) that rapidly interconvert betwe
 en conformations. Unlike structured proteins\, whose behaviours are well-d
 escribed 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 cru
 cial biological processes. Dysregulation of these proteins is therefore im
 plicated in many diseases\, including cancer\, cardiovascular disease\, ty
 pe II diabetes\, and neurodegeneration. Despite their importance\, the cha
 racterization of the structures\, functions\, and pathological roles of di
 sordered proteins is an enormous challenge. In my talk\, I will describe i
 ntegrative methods\, combining molecular dynamics simulations with experim
 ental data from nuclear magnetic resonance spectroscopy to characterise th
 e pathogenicity and druggability of disordered proteins. My talk will high
 light our recent work on the monomeric form of the amyloid-β peptide\, wh
 ose aggregation is a hallmark of Alzheimer's disease. In particular\, I wi
 ll focus on the identification and characterization of a small\, drug-like
  molecule that sequesters amyloid-β in its soluble monomeric form and pre
 vents its toxic aggregation. Using all-atom molecular dynamics simulations
  and biophysical experiment\, we observe the binding interaction to be ext
 remely dynamic\, such that amyloid-β not only remains disordered in the b
 ound form\, but also increases its conformational entropy. A detailed unde
 rstanding of the binding mechanisms between small molecules and disordered
  proteins may lead to the ability to engineer improved interactions\, yiel
 ding drugs targeting these proteins that are highly prevalent in many huma
 n diseases. \n\n
LOCATION:Dept of Chemistry\, Wolfson Lecture Theatre 
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