A Disorder-Aware Computational Framework for Identifying Structurally Tractable EMT Regions in Proliferative Vitreoretinopathy

Abstract Objective /Purpose: 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, AI-enabled computational framework to evaluate EMT-associated proteins in PVR and prioritize structurally tractable regulators for structure-based targeting. Design Computational, hypothesis-generating study employing an in silico screening and structural modeling pipeline. Subjects, Participants, and/or Controls 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, Intervention, or Testing Candidate proteins were evaluated using a multi-stage pipeline integrating intrinsic disorder profiling (RIDAO), redox-sensitive disorder-to-order transition (DOT) analysis (AIUPred), and protein–protein interaction network assessment (STRING). Structure-based modeling and generative binder design were then applied to the top-ranked candidate using RFdiffusion for de novo backbone generation, ProteinMPNN 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 (pLDDT). Results Of the 25 EMT-associated proteins screened, several exhibited intermediate intrinsic disorder profiles and measurable DOT potential. 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 six basic residues with literature-supported or motif-based regulatory significance (K187, R191, R224, K234, K253, 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.