ProDCARL: Reinforcement Learning-Aligned Diffusion Models for De Novo Antimicrobial Peptide Design

TL;DR

ProDCARL is a reinforcement learning framework that enhances diffusion-based peptide generators to design antimicrobial peptides with improved activity and safety, maintaining diversity and structural plausibility.

Contribution

It introduces a reinforcement learning alignment method coupling diffusion models with property predictors for targeted peptide design, a novel approach in this domain.

Findings

Increased mean predicted AMP score from 0.081 to 0.178.

Achieved a 6.3% high-quality hit rate for promising candidates.

Maintained high diversity with 0.929 mean pairwise identity.

Abstract

Antimicrobial resistance threatens healthcare sustainability and motivates low-cost computational discovery of antimicrobial peptides (AMPs). De novo peptide generation must optimize antimicrobial activity and safety through low predicted toxicity, but likelihood-trained generators do not enforce these goals explicitly. We introduce ProDCARL, a reinforcement-learning alignment framework that couples a diffusion-based protein generator (EvoDiff OA-DM 38M) with sequence property predictors for AMP activity and peptide toxicity. We fine-tune the diffusion prior on AMP sequences to obtain a domain-aware generator. Top-k policy-gradient updates use classifier-derived rewards plus entropy regularization and early stopping to preserve diversity and reduce reward hacking. In silico experiments show ProDCARL increases the mean predicted AMP score from 0.081 after fine-tuning to 0.178. The joint high-quality hit rate reaches 6.3\% with pAMP $>$0.7 and pTox $<$0.3. ProDCARL maintains high diversity, with $1-$mean pairwise identity equal to 0.929. Qualitative analyses with AlphaFold3 and ProtBERT embeddings suggest candidates show plausible AMP-like structural and semantic characteristics. ProDCARL serves as a candidate generator that narrows experimental search space, and experimental validation remains future work.