?S-crystallins are water-soluble proteins of eye lens, have paired N-terminal and C-terminal domains with highly compact two Greek-key sandwich motifs. Its stability and the solubility therefore affect vision transparency. Altered stability of ?S-crystallins causes cataract due to aggregation of water-insoluble, misfolded crystallins.    To construct an unfolding pathway of ?S-crystallin, replica exchange MD (REMD) in 260-560 K starting with folded NMR structures was carried out. 2D-PMF was then constructed with an inter-domain distance ILE60...ILE137 and a native-likeness of each domain as reaction coordinates.    The 2D-PMF profile revealed that the domain interface dissociates first upon loss of hydrogen bond network due to small area of interface contact. Then the N-terminal domain is denatured prior to C-terminal domain associated with (a) lacking of the secondary structure of �3, (b) reduction-prone Cys-rich disulfide-bond(s) around �3-�4 causing instability and (c) weakened van der Waals contact triggered by highlyfluctuating long N-terminal arm.

Simulation of age-related cataract causing monomeric two-domain misfolding pathway of γS-crystallin via enhanced sampling and 2D-potential of mean force (2D-PMF) mapping

239th National Meeting (2010)

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