English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Resolving the atomistic modes of anle138b inhibitory action on peptide oligomer formation.

Matthes, D., Gapsys, V., Griesinger, C., & de Groot, B. L. (2017). Resolving the atomistic modes of anle138b inhibitory action on peptide oligomer formation. ACS Chemical Neuroscience, 8(12), 2791-2808. doi:10.1021/acschemneuro.7b00325.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-E7C0-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-9AE0-4
Genre: Journal Article

Files

show Files
hide Files
:
2479296.pdf (Publisher version), 9MB
Name:
2479296.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2479296_Suppl_1.pdf (Supplementary material), 8MB
Name:
2479296_Suppl_1.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2479296_Suppl_2.avi (Supplementary material), 9MB
Name:
2479296_Suppl_2.avi
Description:
-
Visibility:
Public
MIME-Type / Checksum:
video/x-msvideo / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2479296_Suppl_3.avi (Supplementary material), 6MB
Name:
2479296_Suppl_3.avi
Description:
-
Visibility:
Public
MIME-Type / Checksum:
video/x-msvideo / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show

Creators

show
hide
 Creators:
Matthes, D., Author
Gapsys, V.1, Author              
Griesinger, C.2, Author              
de Groot, B. L.1, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

Content

show
hide
Free keywords: amyloid; MD simulations; molecular dynamics; Neurodegenerative diseases; oligomeric aggregate; small molecule inhibitor
 Abstract: The di-phenyl-pyrazole compound anle138b is a known inhibitor of oligomeric aggregate formation in vitro and in vivo. Therefore, anle138b is considered a promising drug candidate to beneficially interfere with neurodegenerative processes causing devastating pathologies in humans. The atomistic details of the aggregation inhibition mechanism, however, are to date unknown since the ensemble of small nonfibrillar aggregates is structurally heterogeneous and inaccessible to direct structural characterization. Here, we set out to elucidate anle138b's mode of action using all-atom molecular dynamics simulations on the multi-microsecond timescale. By comparing simulations of dimeric to tetrameric aggregates from fragments of four amyloidogenic proteins (Aβ, hTau40, hIAPP and Sup35N) in the presence and absence of anle138b, we show that the compound reduces the overall number of intermolecular hydrogen bonds, disfavors the sampling of the aggregated state and remodels the conformational distributions within the small oligomeric peptide aggregates. Most notably, anle138b preferentially interacts with the disordered structure ensemble via its pyrazole moiety, thereby effectively blocking interpeptide main chain interactions and impeding the spontaneous formation of ordered β-sheet structures, in particular those with out-of-register anti-parallel β-strands. The structurally very similar compound anle234b was previously identified as inactive by in vitro experiments. Here, we show that anle234b has no significant effect on the aggregation process in terms of reducing the β-structure content. Moreover, we demonstrate that the hydrogen bonding capabilities are auto-inhibited due to steric effects imposed by the molecular geometry of anle234b and thereby indirectly confirm the proposed inhibitory mechanism of anle138b. We anticipate that the prominent binding of anle138b to partially disordered and dynamical aggregate structures is a generic basis for anle138b's ability to suppress toxic oligomer formation in a wide range of amyloidogenic peptides and proteins.

Details

show
hide
Language(s): eng - English
 Dates: 2017-09-142017-12-20
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acschemneuro.7b00325
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: ACS Chemical Neuroscience
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 8 (12) Sequence Number: - Start / End Page: 2791 - 2808 Identifier: -