Influence of Hyperglycemic Conditions on Self-Association of the Alzheimer's Amyloid β (Aβ1-42 ) Peptide

ACS Omega
Sneha Menon, Neelanjana Sengupta

Abstract

Clinical studies have identified a correlation between type-2 diabetes mellitus and cognitive decrements en route to the onset of Alzheimer's disease (AD). Recent studies have established that post-translational modifications of the amyloid β (Aβ) peptide occur under hyperglycemic conditions; particularly, the process of glycation exacerbates its neurotoxicity and accelerates AD progression. In view of the assertion that macromolecular crowding has an altering effect on protein self-assembly, it is crucial to characterize the effects of hyperglycemic conditions via crowding on Aβ self-assembly. Toward this purpose, fully atomistic molecular dynamics simulations were performed to study the effects of glucose crowding on Aβ dimerization, which is the smallest known neurotoxic species. The dimers formed in the glucose-crowded environment were found to have weaker associations as compared to that of those formed in water. Binding free energy calculations show that the reduced binding strength of the dimers can be mainly attributed to the overall weakening of the dispersion interactions correlated with substantial loss of interpeptide contacts in the hydrophobic patches of the Aβ units. Analysis to discern the differential solvation...Continue Reading

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Citations

Nov 9, 2017·Physical Chemistry Chemical Physics : PCCP·Prapasiri Pongprayoon, Toshifumi Mori
Mar 13, 2018·Physical Chemistry Chemical Physics : PCCP·Andrea Arsiccio, Roberto Pisano
Sep 2, 2020·The Journal of Biological Chemistry·Mahua MaulikJayasri Das Sarma
May 24, 2021·Molecular Biology Reports·Bhoomika SherkhaneShashi Bala Singh
Jun 19, 2021·ACS Biomaterials Science & Engineering·Alex NaftalyDafna Benayahu
Apr 10, 2018·The Journal of Physical Chemistry. B·Sumit MittalElsa Sanchez-Garcia
Aug 11, 2017·Journal of Chemical Information and Modeling·Tingting ZhangJiajie Zhang

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Methods Mentioned

BETA
NMR

Software Mentioned

NAMD
NAMD2
CHARMM
SHIFTS
VMD
Packmol

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