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SUMMARY:Protein Misfolding in rare diseases: Hereditary Transthyretin Amyl
 oidosis - Ugo Lomoio\, Magna Graecia University of Catanzaro
DTSTART:20251017T150000Z
DTEND:20251017T160000Z
UID:TALK234187@talks.cam.ac.uk
CONTACT:Pietro Lio
DESCRIPTION:Transthyretin amyloidosis (ATTR) is a genetically diverse diso
 rder caused by destabilizing mutations in the transthyretin (TTR) protein\
 , leading to pathological aggregation. Although stabilizers such as tafami
 dis and acoramidis are approved\, their efficacy across different TTR vari
 ants remains unclear.\n\nIn this presentation\, we report an in silico pip
 eline that integrates AlphaFold3 for variant structure prediction\, ESM2 f
 or variant classification\, DiffDock-L and AutoDock Vina for molecular doc
 king\, GROMACS for molecular dynamics analysis\, and Diff-SBDD for ligand 
 optimization and generation.\n\nOur results show that the binding affiniti
 es of approved ligands vary significantly across TTR variants\, with some 
 mutations (e.g.\, W61L\, Y98F) reducing binding ability despite being dist
 ant from the T4 binding site of TTR. ESM2 embeddings\, when projected into
  two dimensions using UMAP\, demonstrate clear separation between benign a
 nd pathogenic variants. Projections of benign mutants cluster near wild-ty
 pe TTR\, while pathogenic variants are located farther away. Distances bet
 ween all mutants and wild-type TTR were computed\, and a threshold was app
 lied to perform binary classification\, achieving a ROC AUC of 0.9948.\n\n
 Furthermore\, customized ligand optimization can recover binding affinity 
 in specific destabilizing mutations. For example\, optimization of the taf
 amidis ligand against the Y98F mutation yielded a substantial improvement 
 in both ligand drug-likeness and the overall mutational landscape.\n\nWe a
 lso generated new ligands designed to improve binding at the Y98F-TTR T4 s
 ite. Binding affinities obtained for the most effective generated ligand w
 ere compared with those of acoramidis\, showing improvements across nearly
  all tested mutations.\n\nThis integrative approach provides a foundation 
 for precision drug design in ATTR and may also be applied to other protein
  misfolding disorders\, enabling the development of personalized stabilize
 rs tailored to individual mutational profiles.
LOCATION:Online - Google Meet: https://meet.google.com/jfo-bifc-yjf
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