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SUMMARY:Designing Novel Solenoid Proteins through In Silico Evolution - Dr
  James W Murray
DTSTART:20260213T140000Z
DTEND:20260213T153000Z
UID:TALK244624@talks.cam.ac.uk
CONTACT:Echo Wu Williamson
DESCRIPTION:Solenoid proteins are elongated tandem repeat proteins with di
 verse biological functions\, making them attractive targets for protein de
 sign. Previously\, we made synthetic solenoids drawing residues from conse
 nsus sequence distributions1. Advances in machine learning have transforme
 d our understanding of sequence-structure relationships\, enabling new app
 roaches for de novo protein design. We made an in silico evolution platfor
 m that couples a solenoid discriminator neural network2 with AlphaFold2 as
  an oracle within a genetic algorithm. Starting from random sequences\, we
  select α-\, β-\, and αβ-solenoid backbones\, generating structures th
 at span natural and novel solenoid space. We experimentally characterise 4
 1 solenoid designs\, with α-solenoids consistently folding as intended\, 
 including one structurally validated design that closely matches the desig
 n model3. All β-solenoids initially failed\, reflecting the difficulty of
  designing β-strand majority proteins. By introducing terminal capping el
 ements and refining designs based on earlier experimental screens\, we gen
 erate two β-solenoids that have biophysical properties consistent with th
 eir designs. Our approach achieves fold-specific hallucination-based desig
 n without depending on explicit structural templates.\n\nREFERENCES\n\n1.
     MacDonald\, J. T. et al. Synthetic beta-solenoid proteins with
  the fragment-free computational design of a beta-hairpin extension. Proce
 edings of the National Academy of Sciences 113\, 10346–10351 (2016).\n2.
     Nikov\, G. I.\, Pretorius\, D. & Murray\, J. W. SOLeNNoID: a d
 eep learning pipeline for solenoid residue detection in protein structures
 . Bioinformatics 41\, btaf415 (2025).\n3.    Pretorius\, D. et al.
  Designing novel solenoid proteins with in silico evolution. Commun Chem 9
 \, 10 (2026).
LOCATION:Yusuf Hamied Department of Chemistry\, The Wolfson Lecture Theatr
 e
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