Pyroglutamylation Modulates Electronic Properties and the Conformational
Ensemble of the Amyloid β -Peptide
Abstract
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.