Limitations of pharmacophore modeling for intrinsically disordered plant stress proteins: A case study of DHN1 in Zea mays.

Abstract

Dehydrins are highly conserved drought-responsive proteins that protect plant cells, yet their molecular mode of action remains unclear. In maize (Zea mays), Dehydrin 1 (DHN1) is strongly induced by drought stress and is closely associated with stress-related metabolites including abscisic acid, (ABA), salicylic acid (SA), γ-aminobutyric acid (GABA), β-aminobutyric acid (BABA), and proline. This study assessed the structural feasibility of direct small-molecule binding to DHN1 using molecular docking and pharmacophore-based virtual screening. Disorder prediction confirmed that DHN1 is predominantly intrinsically disordered, with conserved K-segments involved in macromolecular interactions. Docking analyses revealed uniformly weak binding affinities (−2.033 to −2.561 kcal/mol), consistent with non-specific and transient surface contacts. Although pharmacophore modeling modestly improved docking scores, inconsistent binding geometries and poor RMSD convergence indicated a lack of true structural complementarity. These results support the classification of DHN1 as a non-ligand-binding protein that functions primarily through macromolecular stabilization and membrane association, highlighting the need to align computational approaches with protein structural properties in plant stress biology.