{"title":"Microscopic Understandingnof the Conformational Stabilitynof the Aggregated Nonamyloid β Components of α‑Synuclein","authors":"Souvik Mondal (6756170), Krishna Prasad Ghanta (12359218), Sanjoy Bandyopadhyay (1542142)","doi":"10.1021/acs.jcim.2c01540.s001","DOIUrl":"https://doi.org/10.1021/acs.jcim.2c01540.s001","url":null,"abstract":"Self-association of α-synuclein peptides into oligomericnspecies and ordered amyloid fibrils is associated with Parkinson’sndisease, a progressive neurodegenerative disorder. In particular,nthe peptide domain formed between the residues Glu-61 (or E61) andnVal-95 (or V95) of α-synuclein, typically termed the “nonamyloidnβ component” (NAC), is known to play critical roles innforming aggregated structures. In this work, we have employed molecularndynamics simulations to explore the conformational properties andnrelative stabilities of aggregated protofilaments of different orders,nnamely, tetramer (P(4)), hexamer (P(6)), octamer (P(8)), decamer (P(10)),ndodecamer (P(12)), and tetradecamer (P(14)), formed by the NAC domainsnof α-synuclein. Besides, center-of-mass pulling and umbrellansampling simulation methods have also been employed to characterizenthe mechanistic pathway of peptide association/dissociation and thencorresponding free energy profiles. Structural analysis showed thatnthe disordered C-terminal loop and the central <i>core</i> regions of the peptide units lead to more flexible and distortednstructures of the lower order protofilaments (P(4) and P(6)) as comparednto the higher order ones. Interestingly, our calculation shows thenpresence of multiple distinctly populated conformational states fornthe lower order protofilament P(4), which may drive the oligomerizationnprocess along multiple pathways to form different polymorphic α-synucleinnfibrillar structures. It is further observed that the nonpolar interactionnbetween the peptides and the corresponding nonpolar solvation freenenergy play a dominant role in stabilizing the aggregated protofilaments.nImportantly, our result showed that reduced cooperativity during thenbinding of a peptide unit beyond a critical size of the protofilamentn(P(12)) leads to less favorable binding free energy of a peptide.","PeriodicalId":522702,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147901988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}