title: UV-radiation induced disruption of dry-cavities in human γD-crystallin results in decreased stability and faster unfolding.
abstract: Age-onset cataracts are believed to be expedited by the accumulation of UV-damaged human γD-crystallins in the eye lens. Here we show with molecular dynamics simulations that the stability of γD-crystallin is greatly reduced by the conversion of tryptophan to kynurenine due to UV-radiation, consistent with previous experimental evidences. Furthermore, our atomic-detailed results reveal that kynurenine attracts more waters and other polar sidechains due to its additional amino and carbonyl groups on the damaged tryptophan sidechain, thus breaching the integrity of nearby dry center regions formed by the two Greek key motifs in each domain. The damaged tryptophan residues cause large fluctuations in the Tyr-Trp-Tyr sandwich-like hydrophobic clusters, which in turn break crucial hydrogen-bonds bridging two β-strands in the Greek key motifs at the "tyrosine corner". Our findings may provide new insights for understanding of the molecular mechanism of the initial stages of UV-induced cataractogenesis.
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xia
authors.forename: Zaixing
authors.initials: Z
authors.lastname: Yang
authors.forename: Tien
authors.initials: T
authors.lastname: Huynh
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: King
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
mesh_terms: D002386:Cataract / Q000209:etiology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007737:Kynurenine / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics; D056004:Molecular Dynamics Simulation; D055550:Protein Stability / Q000528:radiation effects*; D058767:Protein Unfolding / Q000528:radiation effects*; D014364:Tryptophan / Q000737:chemistry / Q000528:radiation effects*; D014443:Tyrosine / Q000528:radiation effects; D014466:Ultraviolet Rays; D038222:gamma-Crystallins / Q000737:chemistry / Q000528:radiation effects*
chemical_list: C504903:CRYGD protein, human; D038222:gamma-Crystallins; D007737:Kynurenine; D014443:Tyrosine; D014364:Tryptophan