10.1021/acs.biochem.5b00414.s001
Thanh
D. Do
Thanh
D.
Do
Ali Chamas
Ali
Chamas
Xueyun Zheng
Xueyun
Zheng
Aaron Barnes
Aaron
Barnes
Dayna Chang
Dayna
Chang
Tjitske Veldstra
Tjitske
Veldstra
Harmeet Takhar
Harmeet
Takhar
Nicolette Dressler
Nicolette
Dressler
Benjamin Trapp
Benjamin
Trapp
Kylie Miller
Kylie
Miller
Audrene McMahon
Audrene
McMahon
Stephen C. Meredith
Stephen C.
Meredith
Joan-Emma Shea
Joan-Emma
Shea
Kristi Lazar Cantrell
Kristi Lazar
Cantrell
Michael T. Bowers
Michael T.
Bowers
Elucidation of the Aggregation Pathways of Helix–Turn–Helix
Peptides: Stabilization at the Turn Region Is Critical for Fibril
Formation
American Chemical Society
2015
aggregation cascade
fiberlike aggregates
helix
peptide
helical segments
fibril formation
Aggregation Pathways
Fibril FormationAggregation
assembly model
D 26N mutants
D 26 residue decreases
E 21Q
dynamics simulations
2015-07-07 00:00:00
Dataset
https://acs.figshare.com/articles/dataset/Elucidation_of_the_Aggregation_Pathways_of_Helix_Turn_Helix_Peptides_Stabilization_at_the_Turn_Region_Is_Critical_for_Fibril_Formation/2152117
Aggregation
of proteins to fiberlike aggregates often involves
a transformation of native monomers to β-sheet-rich oligomers.
This general observation underestimates the importance of α-helical
segments in the aggregation cascade. Here, using a combination of
experimental techniques and accelerated molecular dynamics simulations,
we investigate the aggregation of a 43-residue, apolipoprotein A-I
mimetic peptide and its E21Q and D26N mutants. Our study indicates
a strong propensity of helical segments not to adopt cross-β-fibrils.
The helix–turn–helix monomeric conformation of the peptides
is preserved in the mature fibrils. Furthermore, we reveal opposite
effects of mutations on and near the turn region in the self-assembly
of these peptides. We show that the E21–R24 salt bridge is
a major contributor to helix–turn–helix folding, subsequently
leading to abundant fibril formation. On the other hand, the K19–D26
interaction is not required to fold the native helix–turn–helix
peptide. However, removal of the charged D26 residue decreases the
stability of the helix–turn–helix monomer and consequently
reduces the level of aggregation. Finally, we provide a more refined
assembly model for the helix–turn–helix peptides from
apolipoprotein A-I based on the parallel stacking of helix–turn–helix
dimers.