Mapping the Conformational Dynamics and Pathways of Spontaneous Steric Zipper Peptide Oligomerization 英文参考文献.docVIP

MappingtheConformationalDynamicsandPathwaysof SpontaneousStericZipperPeptideOligomerization DirkMatthes1,VytautasGapsys1,VenitaDaebel2,BertL.deGroot1* 1Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Go¨ttingen, Germany, 2Solid-State NMR, Max-Planck-Institute for BiophysicalChemistry,Go¨ttingen,Germany Abstract Theprocessofproteinmisfoldingandself-assemblyintovarious,polymorphicaggregatesisassociatedwithanumberof important neurodegenerative diseases. Only recently, crystal structures of several short peptides have provided detailed structuralinsightsintob-sheetrichaggregates,knownasamyloidfibrils.Knowledgeaboutearlyeventsoftheformation andinterconversionofsmalloligomericstates,aninevitablestepinthecascadeofpeptideself-assembly,however,remains stilllimited.Weemploymoleculardynamicssimulationsinexplicitsolventtostudythespontaneousaggregationprocessof steric zipper peptide segments from the tau protein and insulin in atomistic detail. Starting from separated chains with random conformations, we find a rapid formation of structurally heterogeneous, b-sheet rich oligomers, emerging from multiple bimolecular association steps and diverse assembly pathways. Furthermore, our study provides evidence that aggregate intermediates as small as dimers can be kinetically trapped and thus affect the structural evolution of larger oligomers.Alternativeaggregatestructuresarefoundforbothpeptidesequencesinthedifferentindependentsimulations, someofwhichfeaturecharacteristicsoftheknownstericzipperconformation(e.g.,b-sheetbilayerswithadryinterface). Thefinalaggregatesinterconvertwithtopologicallydistinctoligomericstatesexclusivelyviainternalrearrangements.The peptideoligomerizationwasanalyzedthroughtheperspectiveofaminimaloligomer,i.e.,thedimer.Therebyallobserved multimeric aggregates can be consistently mapped onto a space of reduced dimensionality. This novel method of conformational mapping reveals heterogeneous association and reorganizatio