TY  - JOUR
A1  - Miettinen, Markus S.
A1  - Monticelli, Luca
A1  - Nedumpully-Govindan, Praveen
A1  - Knecht, Volker
A1  - Ignatova, Zoya
T1  - Stable polyglutamine dimers can contain beta-hairpins with interdigitated side chains but not a-helices, alpha-nanotubes, beta-pseudohelices, or steric zippers
JF  - Biophysical journal
N2  - A common thread connecting nine fatal neurodegenerative protein aggregation diseases is an abnormally expanded polyglutamine tract found in the respective proteins. Although the structure of this tract in the large mature aggregates is increasingly well described, its structure in the small early aggregates remains largely unknown. As experimental evidence suggests that the most toxic species along the aggregation pathway are the small early ones, developing strategies to alleviate disease pathology calls for understanding the structure of polyglutamine peptides in the early stages of aggregation. Here, we present a criterion, grounded in available experimental data, that allows for using kinetic stability of dimers to assess whether a given polyglutamine conformer can be on the aggregation path. We then demonstrate that this criterion can be assessed using present-day molecular dynamics simulations. We find that although the a-helical conformer of polyglutamine is very stable, dimers of a-helices lack the kinetic stability necessary to support further oligomerization. Dimers of steric zipper, beta-nanotube, and beta-pseudohelix conformers are also too short-lived to initiate aggregation. The beta-hairpin-containing conformers, instead, invariably form very stable dimers when their side chains are interdigitated. Combining these findings with the implications of recent solid-state NMR data on mature fibrils, we propose a possible pathway for the initial stages of polyglutamine aggregation, in which beta-hairpin-containing conformers act as templates for fibril formation.
Y1  - 2014
U6  - https://doi.org/10.1016/j.bpj.2014.02.027
SN  - 0006-3495
SN  - 1542-0086
VL  - 106
IS  - 8
SP  - 1721
EP  - 1728
PB  - Cell Press
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Miettinen, Markus S.
A1  - Knecht, Volker
A1  - Monticelli, Luca
A1  - Ignatova, Zoya
T1  - Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations
JF  - The journal of physical chemistry : B, Condensed matter, materials, surfaces, interfaces & biophysical chemistry
N2  - Polyglutamine (polyQ) diseases comprise a group of dominantly inherited pathology caused by an expansion of an unstable polyQ stretch which is presumed to form beta-sheets. Similar to other amyloid pathologies, polyQ amyloidogenesis occurs via a nucleated polymerization mechanism, and proceeds through energetically unfavorable nucleus whose existence and structure are difficult to detect. Here, we use atomistic molecular dynamics simulations in explicit solvent to assess the conformation of the polyQ stretch in the nucleus that initiates polyQ fibrillization. Comparison of the kinetic stability of various structures of polyQ peptide with a Q-length in the pathological range (Q(40)) revealed that steric zipper or nanotube-like structures (beta-nanotube or beta-pseudohelix) are not kinetically stable enough to serve as a template to initiate polyQ fibrillization as opposed to beta-hairpin-based (beta-sheet and beta-sheetstack) or alpha-helical conformations. The selection of different structures of the polyQ stretch in the aggregation-initiating event may provide an alternative explanation for polyQ aggregate polymorphism.
Y1  - 2012
U6  - https://doi.org/10.1021/jp305065c
SN  - 1520-6106
VL  - 116
IS  - 34
SP  - 10259
EP  - 10265
PB  - American Chemical Society
CY  - Washington
ER  -