Thermodynamics and Kinetics of Aggregation for the GNNQQNY Peptide

Abstract

The energy landscape of the monomer and dimer are explored for the amyloidogenic heptapeptide GNNQQNY from the N-terminal prion-determining domain of the yeast protein Sup35. The peptide is modeled by a united-atom potential and an implicit solvent representation. Replica exchange molecular dynamics is used to explore the conformational space, and discrete path sampling is employed to investigate the pathways that interconvert the most populated minima on the free energy surfaces. For the monomer, we find a rapid fluctuation between four different conformations, where a geometry intermediate between compact and extended structures is the most thermodynamically favorable. The GNNQQNY dimer forms three stable sheet structures, namely in-register parallel, off-register parallel, and antiparallel. The antiparallel dimer is stabilized by strong electrostatic interactions resulting from interpeptide hydrogen bonds, which restrict its conformational flexibility. The in-register parallel dimer, which is close to the amyloid beta-sheet structure, has fewer interpeptide hydrogen bonds, making hydrophobic interactions more important and increasing the conformational entropy compared to the antiparallel sheet. The estimated two-state rate constants indicate that the formation of dimers from monomers is fast and that the dimers are kinetically stable against dissociation at room temperature. Interconversions between the different dimers are feasible processes and are more likely than dissociation.

Factors That Drive Peptide Assembly and Fibril Formation: Experimental and Theoretical Analysis of Sup35 NNQQNY Mutants

“…However, the presence of abundant β-sheet conformations or pre-existing steric zipper structures observed by these methods at small oligomer sizes does not directly imply a high aggregation propensity because the internal rearrangement at large oligomer sizes may be very slow or kinetically inaccessible. 63 Some fibril-crystal distinctions in the packing of the peptide chains within the fiber and crystal forms of GNNQQNY have been shown by studies using diffraction analysis 40 and magic-angle-spinning NMR. 66 A recent elegant model proposed by Knowles and coworkers 67 has addressed the untwisting phenomenon of helical steric zipper during the transition from protofilaments to crystalline phase, which accounts for the discrepancies among the results obtained from measuring the protofilaments and the microcrystals.…”

Dynamics of locking of peptides onto growing amyloid fibrils

“…The isolated Sup35 prion segment peptide is predominantly in a random coil (23,38) [ Fig. 1 and supporting information (SI) Fig.…”

Replica exchange molecular dynamics of the thermodynamics of fibril growth of Alzheimer's Aβ42 peptide

“…21 The growth process has also been probed by various computational studies that study how monomers of Aβ-fragments add to preformed oligomers. [22][23][24][25][26][27] For instance, Buchete and Hummer 28 proposed from all-atom molecular dynamics simulations of Aβ 40 a three-step process, where strong hydrophobic interactions align the C-terminal segments of the incoming peptide with such in the fibril encoura) Electronic mail: minghan2000@gmail.com. b) Electronic mail: hansmann@mtu.edu.…”