A Disorder-Aware Computational Framework to Identify Structurally Tractable Targets in Proliferative Vitreoretinopathy.

Objective: Proliferative vitreoretinopathy (PVR) remains a major cause of failure after rhegmatogenous retinal detachment repair and lacks effective pharmacologic therapies. Although epithelial-mesenchymal transition (EMT) is central to PVR pathogenesis, the structural determinants governing the tractability of EMT regulators, particularly those involving intrinsic disorder, remain poorly defined. We developed a disorder-aware, artificial intelligence-enabled computational framework to evaluate EMT-associated proteins in PVR and prioritize structurally tractable regulators for structure-based targeting. Design: A computational, hypothesis-generating study employing an in silico screening and structural modeling pipeline. Subjects: No human subjects or biological specimens were included. The dataset comprised 25 EMT-associated proteins implicated in PVR, curated through a narrative review of peer-reviewed literature. Methods: Candidate proteins were evaluated using a multistage pipeline integrating intrinsic disorder profiling (Rapid Intrinsic Disorder Analysis Online), redox-sensitive disorder-to-order transition (DOT) analysis (AIUPred), and protein-protein interaction network assessment (Search Tool for the Retrieval of Interacting Genes/Proteins [STRING]). Structure-based modeling and generative binder design were then applied to the top-ranked candidate using RFdiffusion for de novo backbone generation, protein message passing neural network for sequence design, and AlphaFold2 for structural validation. Main Outcome Measures: Primary measures were the proportion of intrinsically disordered residues, redox-sensitive disorder change, STRING network coherence within EMT-related pathways, and the structural consistency of the designed binder-target complex, assessed by root mean square deviation (RMSD) and mean per-residue confidence (predicted local distance difference test [pLDDT]). Results: Of the 25 EMT-associated proteins screened, several exhibited intermediate intrinsic disorder profiles and measurable DOT potential. Snail Family Transcriptional Repressor 1 (SNAIL1) emerged as the highest-priority candidate, demonstrating an intermediate intrinsic disorder profile (∼35%), a pronounced redox-sensitive DOT region, and selective connectivity within EMT-related signaling networks. Functional mapping of the SNAIL1 C-terminal DOT segment identified 6 basic residues with literature-supported or motif-based regulatory significance (K187, R191, R224, K234, K253, and R264). Following sequence design and structural validation, the top-ranked binder exhibited the lowest structural deviation within the generated ensemble (RMSD 18.5 Å) and high per-residue confidence (mean pLDDT 0.84). Conclusions: Our study introduces a disorder-informed computational framework for prioritizing structurally tractable EMT regulators in PVR. As a proof-of-concept, the pipeline nominates SNAIL1 and generates a structure-aware de novo binder targeting its C-terminal DOT region, providing a foundation for disorder-based therapeutic discovery in fibrotic retinal disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.