UV-radiation Induced Disruption of Tightly Packed Dry Cavities in Human γD-crystallin Results in Decreased Stability and Faster Unfolding

Zhen Xia, Zaixing Yang, Tien Huynh, Jonathan A. King, andRuhong Zhou*

(Nature) Sci. Rep. 3, 1560, 2013

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 large-scale 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 cavities 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.

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链接：http://www.nature.com/srep/2013/130327/srep01560/full/srep01560.html