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Pyroglutamylation Modulates Electronic Properties and the Conformational Ensemble of the Amyloid β -Peptide
  • Justin Lemkul,
  • Darcy S. Davidson
Justin Lemkul
Virginia Polytechnic Institute and State University Department of Biochemistry

Corresponding Author:[email protected]

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Darcy S. Davidson
Virginia Polytechnic Institute and State University Department of Biochemistry
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Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by the formation of extracellular amyloid- β (A β) plaques. The underlying cause of AD is unknown, however, post-translational modifications (PTMs) of A β have been found in AD patients and are thought to play a role in protein aggregation. One such PTM is pyroglutamylation, which can occur at two sites in A β, Glu3 and Glu11. This modification of A β involves the truncation and charge-neutralization of N-terminal glutamate, causing A β to become more hy- drophobic and prone to aggregation. The molecular mech- anism by which the introduction of pyroglutamate (pE) pro- motes aggregation has not been determined. To gain a greater understanding of the role that charge neutralization and trun- cation of the N-terminus plays on A β conformational sam- pling, we used the Drude polarizable force field (FF) to per- form molecular dynamics simulations on A β pE3-42 and A β pE11-42 and comparing their properties to previous simulations of A β 1-42. The Drude polarizable FF allows for a more accurate representation of electrostatic interactions, therefore pro- viding novel insights into the role that charge plays in pro- tein dynamics. Here, we report the parametrization of pE in the Drude polarizable FF and the effect of pyroglutamyla- tion on A β. We found that A β pE3-42 and A β pE11-42 alter the permanent and induced dipoles of the peptide. Specifically, we found that A β pE3-42 and A β pE11-42 have modification- specific backbone and sidechain polarization response and perturbed solvation properties that shift the A β conforma- tional ensemble.
20 Nov 2023Submitted to PROTEINS: Structure, Function, and Bioinformatics
20 Nov 2023Submission Checks Completed
20 Nov 2023Assigned to Editor
20 Nov 2023Review(s) Completed, Editorial Evaluation Pending
21 Nov 2023Reviewer(s) Assigned
31 Jan 20241st Revision Received
31 Jan 2024Submission Checks Completed
31 Jan 2024Assigned to Editor
31 Jan 2024Review(s) Completed, Editorial Evaluation Pending
31 Jan 2024Reviewer(s) Assigned
08 Feb 2024Editorial Decision: Accept