Effects of Ions and Small Compounds on the Structure of Aβ42Monomers
Document Type
Article
Publication Date
2-4-2021
Abstract
Aggregation of amyloid-β (Aβ) proteins in the brain is a hallmark of Alzheimer's disease. This phenomenon can be promoted or inhibited by adding small molecules to the solution where Aβ is embedded. These molecules affect the ensemble of conformations sampled by Aβ monomers even before aggregation starts. Here, we perform extensive all-atom replica exchange molecular dynamics (REMD) simulations to provide a comparative study of the ensemble of conformations sampled by Aβ42 monomers in solutions that promote (i.e., aqueous solution containing NaCl) and inhibit (i.e., aqueous solutions containing scyllo-inositol or 4-aminophenol) aggregation. Simulations performed in pure water are used as our reference. We find that secondary-structure content is only affected in an antagonistic manner by promoters and inhibitors at the C-terminus and the central hydrophilic core. Moreover, the end of the C-terminus binds more favorably to the central hydrophobic core region of Aβ42 in NaCl adopting a type of strand-loop-strand structure that is disfavored by inhibitors. Nonpolar residues that form the dry core of larger aggregates of Aβ42 (e.g., PDB ID 2BEG) are found at close proximity in these strand-loop-strand structures, suggesting that their formation could play an important role in initiating nucleation. In the presence of inhibitors, the C-terminus binds the central hydrophilic core with a higher probability than in our reference simulation. This sensitivity of the C-terminus, which is affected in an antagonistic manner by inhibitors and promoters, provides evidence for its critical role in accounting for aggregation.
Identifier
85100275755 (Scopus)
Publication Title
Journal of Physical Chemistry B
External Full Text Location
https://doi.org/10.1021/acs.jpcb.0c09617
e-ISSN
15205207
ISSN
15206106
PubMed ID
33481611
First Page
1085
Last Page
1097
Issue
4
Volume
125
Grant
CHE-1904364
Fund Ref
National Science Foundation
Recommended Citation
Mahmoudinobar, Farbod; Nilsson, Bradley L.; and Dias, Cristiano L., "Effects of Ions and Small Compounds on the Structure of Aβ42Monomers" (2021). Faculty Publications. 4331.
https://digitalcommons.njit.edu/fac_pubs/4331