Abstract
Human γD-crystallin (HGDC) is an abundant lens protein residing in the nucleus of the human lens. Aggregation of this and other structural proteins within the lens leads to the development of cataract. Much has been explored on the stability and aggregation of HGDC and where detailed investigation at the atomic resolution was needed, the X-ray structure was used as an initial starting conformer for molecular modeling. In this study, we implemented NMR-solution HGDC structures as starting conformers for molecular dynamics simulations to provide the missing pieces of the puzzle on the very early stages of HGDC unfolding leading up to the domain swap theories proposed by past studies. The high-resolution details of the conformational dynamics also revealed additional insights to possible early intervention for cataractogenesis.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
In the previous studies [17,18], we have predicted the region of HGDC that may be involved in its aggregation process under low-pH conditions by molecular dynamics (MD) simulations using the X-ray crystal structure of HGDC as a starting structure
We applied a similar approach to predict the unstable regions of HGDC and to examine the sequence of initial unfolding events that may lead to misfolding, and result in HGDC aggregation
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations Proteins, in their native forms, are essential biological macromolecules taking on various biological roles in physiochemical processes. They can play a structural role by being in a natively well-defined folded state to retain order in the body and achieve specialized function, such as maintaining clear vision One such protein is human γD-crystallin (HGDC), a predominant protein of the eye lens nucleus. Three solution-NMR structures, native and high energy state structures obtained from denaturing solutions (urea and GdnHCl), were submitted for molecular dynamics (MD) simulations in a water solvent to understand the structural changes these proteins may undertake during the process of refolding/misfolding when removed from the denaturing environment. NMR structures of HGDC as starting structures to compare and contrast the dynamics of the structural changes arising from different co-solvent environments
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