Issue 24, 2021

Lanosterol reduces the aggregation propensity of ultraviolet-damaged human γD-crystallins: a molecular dynamics study

Abstract

Ultraviolet (UV) radiation-induced oxidation of tryptophan (Trp) to kynurenine (KN) (TRP > KN) in human γD-crystallins (HγD-Crys) promotes the conversion of proteins into partially unfolded species that act as important precursors for sequential large-scale aggregation. Herein, we report that lanosterol shows protective activity to the structure of the TRP > KN mutant HγD-Crys, particularly its N-terminal domain (N-td), by using all-atom molecular dynamics simulations. The Trp68 > KN mutation significantly destabilizes the originally highly stable “Tyr55–Trp68–Tyr62” cluster, thereby causing loop2, where the mutation occurs, to become very flexible. The large fluctuation of loop2 induces cracks, which appear on the protein surface, resulting in the intrusion of water molecules into the hydrophobic core of the N-td. This event eventually triggers the unfolding of the N-td. However, lanosterol can suppress the large fluctuation of loop2 to protect the structural stability of the mutant N-td, thus reducing the aggregation propensity of the TRP > KN mutant HγD-Crys. This structure protective activity of lanosterol arises from its capability to preferentially bind to the hydrophobic regions near loop2. Thus, lanosterol acts as a “water blocker” to prevent the invasion of solvent molecules into the hydrophobic core. These findings provide some valuable insights into the development of potential lanosterol-based drugs for cataract prevention and treatment.

Graphical abstract: Lanosterol reduces the aggregation propensity of ultraviolet-damaged human γD-crystallins: a molecular dynamics study

Supplementary files

Article information

Article type
Paper
Submitted
11 Jan 2021
Accepted
27 May 2021
First published
27 May 2021

Phys. Chem. Chem. Phys., 2021,23, 13696-13704

Lanosterol reduces the aggregation propensity of ultraviolet-damaged human γD-crystallins: a molecular dynamics study

H. Zhou, Y. Li, Y. Yang, S. Liu and Z. Yang, Phys. Chem. Chem. Phys., 2021, 23, 13696 DOI: 10.1039/D1CP00132A

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements