Biology subjects

Vure, P.

Publications and source records attributed to Vure, P..

3 recordsLinked to original sources

bioRxiv2024

FusOn-pLM: A Fusion Oncoprotein-Specific Language Model via Focused Probabilistic Masking

Fusion oncoproteins, a class of chimeric proteins arising from chromosomal translocations, drive and sustain various cancers, particularly those impacting children. Unfortunately, due to their intrinsically disordered nature, large size, and lack of well-defined, druggable pockets, they have been historically challenging to target therapeutically: neither small molecule-based methods nor structure-based approaches for binder design are strong options for this class of molecules. Recently, protein language models (pLMs) have demonstrated success at representing protein sequences with information-rich embeddings, enabling downstream design applications from sequence alone. However, no current pLM has been trained on fusion oncoprotein sequences and thus may not produce optimal representations for these proteins. In this work, we introduce FusOn-pLM, a novel pLM that fine-tunes the state-of-the-art ESM-2 model on fusion oncoprotein sequences. We specifically introduce a novel masked language modeling (MLM) strategy, employing a binding-site probability predictor to focus masking on key amino acid residues, thereby generating more optimal fusion oncoprotein-aware embeddings. Our model improves performance on both fusion oncoprotein-specific benchmarks and disorder prediction tasks in comparison to baseline ESM-2 representations, as well as manually-constructed biophysical embeddings, motivating downstream usage of FusOn-pLM embeddings for therapeutic design tasks targeting these fusions. We have made our model publicly available to the community at https://huggingface.co/ChatterjeeLab/FusOn-pLM.

bioinformatics↗

bioRxiv2024

AMP-Diffusion: Integrating Latent Diffusion with Protein Language Models for Antimicrobial Peptide Generation

Denoising Diffusion Probabilistic Models (DDPMs) have emerged as a potent class of generative models, demonstrating exemplary performance across diverse AI domains such as computer vision and natural language processing. In the realm of protein design, while there have been advances in structure-based, graph-based, and discrete sequence-based diffusion, the exploration of continuous latent space diffusion within protein language models (pLMs) remains nascent. In this work, we introduce AMP-Diffusion, a latent space diffusion model tailored for antimicrobial peptide (AMP) design, harnessing the capabilities of the state-of-the-art pLM, ESM-2, to de novo generate functional AMPs for downstream experimental application. Our evaluations reveal that peptides generated by AMP-Diffusion align closely in both pseudo-perplexity and amino acid diversity when benchmarked against experimentally-validated AMPs, and further exhibit relevant physicochemical properties similar to these naturally-occurring sequences. Overall, these findings underscore the biological plausibility of our generated sequences and pave the way for their empirical validation. In total, our framework motivates future exploration of pLM-based diffusion models for peptide and protein design.

bioinformatics↗

bioRxiv2023

Engineered Immunogens to Expose Conserved Epitopes Targeted by Broad Coronavirus Antibodies

Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which continually mutates to escape acquired immunity. Other regions in the spike S2 subunit, such as the stem helix and the segment encompassing residues 815-823 adjacent to the fusion peptide, are highly conserved across sarbecoviruses and are recognized by broadly reactive antibodies, providing hope that vaccines targeting these epitopes could offer protection against both current and emergent viruses. Here we employed computational modeling to design scaffolded immunogens that display the spike 815-823 peptide and the stem helix epitopes without the distracting and immunodominant RBD. These engineered proteins bound with high affinity and specificity to the mature and germline versions of previously identified broadly protective human antibodies. Epitope scaffolds interacted with both sera and isolated monoclonal antibodies with broadly reactivity from individuals with pre-existing SARS-CoV-2 immunity. When used as immunogens, epitope scaffolds elicited sera with broad betacoronavirus reactivity and protected as "boosts" against live virus challenge in mice, illustrating their potential as components of a future pancoronavirus vaccine.

immunology↗