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Peptide binder desi...
Peptide binder design with inverse folding and protein structure prediction
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- Bryant, Patrick (författare)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
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- Elofsson, Arne, 1966- (författare)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)
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(creator_code:org_t)
- 2023
- 2023
- Engelska.
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Ingår i: Communications Chemistry. - 2399-3669. ; 6:1
- Relaterad länk:
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https://doi.org/10.1...
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visa fler...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- The computational design of peptide binders towards a specific protein interface can aid diagnostic and therapeutic efforts. Here, we design peptide binders by combining the known structural space searched with Foldseek, the protein design method ESM-IF1, and AlphaFold2 (AF) in a joint framework. Foldseek generates backbone seeds for a modified version of ESM-IF1 adapted to protein complexes. The resulting sequences are evaluated with AF using an MSA representation for the receptor structure and a single sequence for the binder. We show that AF can accurately evaluate protein binders and that our bind score can select these (ROC AUC = 0.96 for the heterodimeric case). We find that designs created from seeds with more contacts per residue are more successful and tend to be short. There is a relationship between the sequence recovery in interface positions and the plDDT of the designs, where designs with >= 80% recovery have an average plDDT of 84 compared to 55 at 0%. Designed sequences have 60% higher median plDDT values towards intended receptors than non-intended ones. Successful binders (predicted interface RMSD <= 2 angstrom) are designed towards 185 (6.5%) heteromeric and 42 (3.6%) homomeric protein interfaces with ESM-IF1 compared with 18 (1.5%) using ProteinMPNN from 100 samples. Designing peptides that bind to specific protein targets is crucial for peptidic drug development, however, traditional computer-aided binder design is outperformed by AlphaFold2. Here, the authors develop a peptide binder designing tool by combining Foldseek, ESM-IF1 and AlphaFold2 to increase the success rate.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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