ArticleResearch square2025
In Silico Modelling of the AQP0 T138R Mutation and its' links to Potential Mechanisms of Cataractogenesis.
Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The T138R mutation in Aquaporin 0 (AQP0), a key membrane protein in the ocular lens, causes autosomal dominant congenital cataracts. Whilst previous studies have demonstrated that this mutation disrupts water permeability and leads to protein mislocalisation, the specific structural mechanisms underlying these functional defects remain unclear. This study employed in silico approaches to characterise how the T138R substitution affects AQP0's molecular structure and stability. Computational analysis revealed that whilst the mutation does not significantly alter the protein's global conformation (RMSD = 0.000 Å), it may disrupt a key network of hydrogen bonds involving Glu134, Ile135, and Pro208. Multiple sequence alignment showed these interacting residues are highly conserved across species, underscoring their structural or functional importance. Hydrophobicity analysis indicated that the substitution resulted in a strongly hydrophilic, positively charged residue (Arg, Kyte-Doolittle score: -4.5) into a predominantly hydrophobic transmembrane environment. Transmembrane insertion energetics calculations demonstrated a possible increase for membrane integration (ΔGpredapp: +1.42 to + 1.63 kcal/mol), with the Arg side chain contributing nearly twice the insertion cost of Thr (+ 0.23 vs. +0.41 kcal/mol). Protein-protein interaction modelling with Connexin 50 revealed subtle but potentially significant changes at the docking interface, including potential decreased solvent-excluded surface (-0.00019646) and increased solvent-accessible surface (+ 0.00062829) changes. Additionally, potential steric clashes between Arg138 and Met183 were identified. These findings suggested reduced compactness, possible formation of internal voids and disruption of local packing. This work provided insight into the structural changes that may underlie the functional impairments of AQP0, supporting future research into its role in cataract formation.
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