分子動力学シミュレーションによるヒトγDクリスタリンR58H変異の構造的特性解析
Crystallin proteins, expressed as monomers in the mammalian lens, are prone to mutation-induced aggregation that underlies various cataract subtypes. This computational study examined the structural consequences of the R58H substitution in γD crystallin via molecular dynamics (MD) simulation. The analysis revealed substantial variation in backbone atomic positions between the mutant and wild-type forms, accompanied by altered conformational rigidity. Increased intramolecular hydrogen bonding in the R58H mutant was associated with misfolding events, including the introduction of α-helical secondary structure. Principal component analysis demonstrated that the mutant exhibited aberrant conformational dynamics along two principal components relative to wild-type γD crystallin. Elevated surface hydrophobicity in the mutant was identified as a probable driver of self-aggregation, potentially explaining the aculeiform cataract phenotype linked to this mutation.
The R58H substitution increases intramolecular hydrogen bonding and introduces α-helical structure, causing misfolding; elevated surface hydrophobicity then drives self-aggregation of γD crystallin.
This is basic research at the cellular or molecular level. For human application, inhalation is the most promising delivery route, but inhalation carries explosion risk and concentration matters (empirical LFL of 10%; high-concentration devices are not recommended).
See also:
https://h2-papers.org/en/papers/29532225