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Masked Diffusion Language Models (MDLMs) have recently emerged as a strong class of generative models, paralleling state-of-the-art (SOTA) autoregressive (AR) performance across natural language modeling domains. While there have been advances in AR as well as both latent and discrete diffusion-based approaches for protein sequence design, masked diffusion language modeling with protein language models (pLMs) is unexplored. In this work, we introduce MeMDLM, an MDLM tailored for membrane protein design, harnessing the SOTA pLM ESM-2 to de novo generate realistic membrane proteins for downstream experimental applications. Our evaluations demonstrate that MeMDLM-generated proteins exceed AR-based methods by generating sequences with greater transmembrane (TM) character. We further apply our design framework to scaffold soluble and TM motifs in sequences, demonstrating that MeMDLM-reconstructed sequences achieve greater biological similarity to their original counterparts compared to SOTA inpainting methods. Finally, we show that MeMDLM captures physicochemical membrane protein properties with similar fidelity as SOTA pLMs, paving the way for experimental applications. In total, our pipeline motivates future exploration of MDLM-based pLMs for protein design.

Target proteins that lack accessible binding pockets and conformational stability have posed increasing challenges for drug development. Induced proximity strategies, such as PROTACs and molecular glues, have thus gained attention as pharmacological alternatives, but still require small molecule docking at binding pockets for targeted protein degradation. The computational design of protein-based binders presents unique opportunities to access "undruggable" targets, but have often relied on stable 3D structures or structure-influenced latent spaces for effective binder generation. In this work, we introduce PepMLM, a target sequence-conditioned generator of de novo linear peptide binders. By employing a novel span masking strategy that uniquely positions cognate peptide sequences at the C-terminus of target protein sequences, PepMLM fine-tunes the state-of-the-art ESM-2 pLM to fully reconstruct the binder region, achieving low perplexities matching or improving upon validated peptide-protein sequence pairs. After successful in silico benchmarking with AlphaFold-Multimer, outperforming RFDiffusion on structured targets, we experimentally verify PepMLM's efficacy via fusion of model-derived peptides to E3 ubiquitin ligase domains, demonstrating endogenous degradation of emergent viral phosphoproteins and Huntington's disease-driving proteins. In total, PepMLM enables the generative design of candidate binders to any target protein, without the requirement of target structure, empowering downstream therapeutic applications.