Document Type
Article
Publication Date
5-25-2026
Abstract
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.
Recommended Citation
Djulbegovic, Mak B.; Hadzijahic, Nedym; Taylor Gonzalez, David J.; Antonietti, Michael; Zafar, Sidra; and Kuriyan, Ajay E., "A Disorder-Aware Computational Framework to Identify Structurally Tractable Targets in Proliferative Vitreoretinopathy" (2026). Wills Eye Hospital Papers. Paper 305.
https://jdc.jefferson.edu/willsfp/305
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
42421755
Language
English
Comments
This article is the author’s final published version in Ophthalmology Science, Volume 6, Issue 8, 2026, Article number 101249.
The published version is available at https://doi.org/10.1016/j.xops.2026.101249. Copyright © 2026 American Academy of Ophthalmology, Inc .