Layne, E. | Search bioRxiv

bioRxiv2025

Improved De Novo Peptide Binder Design with Target-Conditioned Inverse Folding

Inverse protein folding methods have become central to the computational design of de novo proteins, but existing models struggle when tasked with generating high-affinity peptide binders. By combining peptide-specific finetuning with a novel decoding order strategy, we enhance pocket conditioning and enable more accurate sequence design for peptide-binding interfaces. Our approach delivers gains in computational metrics, increasing sequence recovery and improving in silico binder design success rate by 16% 30%. In vitro validation finds that our method greatly improves the success rate of designing novel peptide agonists of the OPRM1 receptor, generating at least twice as many top-ranking agonists as the prevailing standard method ProteinMPNN.

bioengineering↗

bioRxiv2024

Multi-ancestry polygenic risk scores using phylogenetic regularization

Accurately predicting phenotype using genotype across diverse ancestry groups remains a significant challenge in human genetics. Many state-of-the-art polygenic risk score models are known to have difficulty generalizing to genetic ancestries that are not well represented in their training set. To address this issue, we present a novel machine learning method for fitting genetic effect sizes across multiple ancestry groups simultaneously, while leveraging prior knowledge of the evolutionary relationships among them. We introduce DendroPRS, a machine learning model where SNP effect sizes are allowed to evolve along the branches of the phylogenetic tree capturing the relationship among populations. DendroPRS outperforms existing approaches at two important genotype-to-phenotype prediction tasks: expression QTL analysis and polygenic risk scores. We also demonstrate that our method can be useful for multiancestry modelling, both by fitting population-specific effect sizes and by more accurately accounting for covariate effects across groups. We additionally find a subset of genes where there is strong evidence that an ancestry-specific approach improves eQTL modelling.

bioinformatics↗