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Download fileLanosterol Disrupts Aggregation of Human γD-Crystallin by Binding to the Hydrophobic Dimerization Interface
journal contribution
posted on 2018-06-19, 00:00 authored by Hongsuk Kang, Zaixing Yang, Ruhong ZhouCataracts are a leading cause of
vision impairment, which stem
from the misfolding and aggregation of crystallins in the eye lens.
Despite its prevalence and severity, the detailed mechanism by which
misfolded crystallins aggregate into cataracts remains elusive. Recently, in vitro and in vivo experiments demonstrated
that lanosterol, a steroid-type compound found in human and animal
eyes, can not only prevent cataract formation but also reverse
the formation. Inspired by these experimental observations, we investigate
the preventive activity of lanosterol in the aggregate formation of
human γD-crystallins (HγD-Crys) using all atom molecular
dynamics (MD) simulation and free energy perturbation (FEP) techniques.
Our results reveal that lanosterol preferentially binds to the HγD-Crys
hydrophobic dimerization interface, in particular, to the structured
C-terminus (near residues 135–165) with a stronger binding
affinity than the unfolded N-terminus. Furthermore, we observe that
the C-terminal binding is more favorable than lanosterol self-aggregation,
further attesting to lanosterol’s efficacy. Finally, we compare
the binding free energy of lanosterol with cholesterol using alchemical
transformation and discuss the possible correlation of the molecular
geometry of steroids with binding affinity.