{"doi":"10.1021/jacs.1c06339","title":"Constraints on the Structure of Fibrils Formed by a Racemic Mixture of Amyloid-β Peptides from Solid-State NMR, Electron Microscopy, and Theory","abstract":"Previous studies have shown that racemic mixtures of 40- and 42-residue amyloid-β peptides (d,l-Aβ40 and d,l-Aβ42) form amyloid fibrils with accelerated kinetics and enhanced stability relative to their homochiral counterparts (l-Aβ40 and l-Aβ42), suggesting a “chiral inactivation” approach to abrogating the neurotoxicity of Aβ oligomers (Aβ-CI). Here we report a structural study of d,l-Aβ40 fibrils, using electron microscopy, solid-state nuclear magnetic resonance (NMR), and density functional theory (DFT) calculations. Two- and three-dimensional solid-state NMR spectra indicate molecular conformations in d,l-Aβ40 fibrils that resemble those in known l-Aβ40 fibril structures. However, quantitative measurements of 13C–13C and 15N–13C distances in selectively labeled d,l-Aβ40 fibril samples indicate a qualitatively different supramolecular structure. While cross-β structures in mature l-Aβ40 fibrils are comprised of in-register, parallel β-sheets, our data indicate antiparallel β-sheets in d,l-Aβ40 fibrils, with alternation of d and l molecules along the fibril growth direction, i.e., antiparallel “rippled sheet” structures. The solid-state NMR data suggest the coexistence of d,l-Aβ40 fibril polymorphs with three different registries of intermolecular hydrogen bonds within the antiparallel rippled sheets. DFT calculations support an energetic preference for antiparallel alignments of the β-strand segments identified by solid-state NMR. These results provide insight into the structural basis for Aβ-CI and establish the importance of rippled sheets in self-assembly of full-length, naturally occurring amyloidogenic peptides.","journal":"Journal of the American Chemical Society","year":2021,"id":170225,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":444180,"name":"Alejandro R. Foley","orcid":"0000-0002-8644-0546","position":1,"is_corresponding":false},{"id":458319,"name":"John M. Louis","orcid":"0000-0002-0052-1899","position":2,"is_corresponding":false},{"id":337240,"name":"Wai‐Ming Yau","orcid":"0000-0002-7668-7780","position":3,"is_corresponding":false},{"id":272110,"name":"Robert Tycko","orcid":"0000-0001-7039-7275","position":4,"is_corresponding":false},{"id":168288,"name":"Jevgenij A. Raskatov","orcid":"0000-0002-0082-9113","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-18T23:46:19.728805Z","pmid":"34375097","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}