A Molecular Dynamics Perspective To Identify Precursors to Aggregation in Human γS-Crystallin Unravels the Mechanism of Childhood CataractsClick to copy article linkArticle link copied!
- Khandekar Jishan Bari*Khandekar Jishan Bari*E-mail: [email protected]Center for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Hyderabad, Telangana 500107, IndiaMore by Khandekar Jishan Bari
- Dheeraj Dube*Dheeraj Dube*E-mail: [email protected]Center for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Hyderabad, Telangana 500107, IndiaMore by Dheeraj Dube
- Shrikant Sharma*Shrikant Sharma*E-mail: [email protected]Center for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Hyderabad, Telangana 500107, IndiaDepartment of Chemistry, University of Washington, Seattle, Washington 98195, United StatesMore by Shrikant Sharma
- Kandala V. R. Chary*Kandala V. R. Chary*E-mail: [email protected]; [email protected]Indian Institute of Science Education and Research, Berhampur, Odisha 760010, IndiaMore by Kandala V. R. Chary
Abstract
Despite the increasing health risk from infantile cataracts, identifying the mechanism of this disease remains a challenge due to a lack of structural investigations using experimental and computational approaches. Mutations in human γS-crystallin are contingent with childhood cataracts. Our recent high-resolution structural studies using solution NMR spectroscopy established the key role of the G57W mutation in human γS-crystallin (abbreviated hereafter as γS-G57W), promoting structural instability. In order to design therapeutics to delay or upset congenital cataracts, the characterization of the precursors to γS-G57W aggregation is indispensable. In this endeavor, we present microsecond long unbiased atomistic molecular dynamics simulations and principal component analyses that unfold insights into lens crystallin aggregation. An enhanced sampling metadynamics approach was further employed to systematically unravel the molecular dynamics underlying crucial interdomain contacts. Taken together, our experiment-guided computational study in this paper led to the identification of domain-swapped intermediates in γS-G57W to atomic resolution with insights into the aggregation of lens crystallins causing childhood cataracts for the first time with functional consequences.
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This article is cited by 7 publications.
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, 1644-1656. https://doi.org/10.1021/acs.jpclett.0c03404
- Khandekar Jishan Bari, Shrikant Sharma. A Perspective on Biophysical Studies of Crystallin Aggregation and Implications for Cataract Formation. The Journal of Physical Chemistry B 2020, 124
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, 11041-11054. https://doi.org/10.1021/acs.jpcb.0c07449
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- Khandekar Jishan Bari. The structural biology of crystallin aggregation: challenges and outlook. The FEBS Journal 2021, 288
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, 5888-5902. https://doi.org/10.1111/febs.15684
- José-Luis Velasco-Bolom, Laura Domínguez. Exploring the folding process of human βB2-crystallin using multiscale molecular dynamics and the Markov state model. Physical Chemistry Chemical Physics 2020, 22
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