TY - JOUR
T1 - Cooperative structural transitions in amyloid-like aggregation
AU - Steckmann, Timothy
AU - Bhandari, Yuba R.
AU - Chapagain, Prem P.
AU - Gerstman, Bernard S.
N1 - Publisher Copyright:
© 2017 Author(s).
PY - 2017/4/7
Y1 - 2017/4/7
N2 - Amyloid fibril aggregation is associated with several horrific diseases such as Alzheimer’s, Creutzfeld-Jacob, diabetes, Parkinson’s, and others. Although proteins that undergo aggregation vary widely in their primary structure, they all produce a cross-β motif with the proteins in β-strand conformations perpendicular to the fibril axis. The process of amyloid aggregation involves forming myriad different metastable intermediate aggregates. To better understand the molecular basis of the protein structural transitions and aggregation, we report on molecular dynamics (MD) computational studies on the formation of amyloid protofibrillar structures in the small model protein ccβ, which undergoes many of the structural transitions of the larger, naturally occurring amyloid forming proteins. Two different structural transition processes involving hydrogen bonds are observed for aggregation into fibrils: the breaking of intrachain hydrogen bonds to allow β-hairpin proteins to straighten, and the subsequent formation of interchain H-bonds during aggregation into amyloid fibrils. For our MD simulations, we found that the temperature dependence of these two different structural transition processes results in the existence of a temperature window that the ccβ protein experiences during the process of forming protofibrillar structures. This temperature dependence allows us to investigate the dynamics on a molecular level. We report on the thermodynamics and cooperativity of the transformations. The structural transitions that occurred in a specific temperature window for ccβ in our investigations may also occur in other amyloid forming proteins but with biochemical parameters controlling the dynamics rather than temperature.
AB - Amyloid fibril aggregation is associated with several horrific diseases such as Alzheimer’s, Creutzfeld-Jacob, diabetes, Parkinson’s, and others. Although proteins that undergo aggregation vary widely in their primary structure, they all produce a cross-β motif with the proteins in β-strand conformations perpendicular to the fibril axis. The process of amyloid aggregation involves forming myriad different metastable intermediate aggregates. To better understand the molecular basis of the protein structural transitions and aggregation, we report on molecular dynamics (MD) computational studies on the formation of amyloid protofibrillar structures in the small model protein ccβ, which undergoes many of the structural transitions of the larger, naturally occurring amyloid forming proteins. Two different structural transition processes involving hydrogen bonds are observed for aggregation into fibrils: the breaking of intrachain hydrogen bonds to allow β-hairpin proteins to straighten, and the subsequent formation of interchain H-bonds during aggregation into amyloid fibrils. For our MD simulations, we found that the temperature dependence of these two different structural transition processes results in the existence of a temperature window that the ccβ protein experiences during the process of forming protofibrillar structures. This temperature dependence allows us to investigate the dynamics on a molecular level. We report on the thermodynamics and cooperativity of the transformations. The structural transitions that occurred in a specific temperature window for ccβ in our investigations may also occur in other amyloid forming proteins but with biochemical parameters controlling the dynamics rather than temperature.
UR - http://www.scopus.com/inward/record.url?scp=85017251166&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017251166&partnerID=8YFLogxK
U2 - 10.1063/1.4979516
DO - 10.1063/1.4979516
M3 - Article
C2 - 28390382
AN - SCOPUS:85017251166
SN - 0021-9606
VL - 146
JO - Journal of Chemical Physics
JF - Journal of Chemical Physics
IS - 13
M1 - 135103
ER -