{"doi":"10.1039/d3sc06245g","title":"<i>De novo</i> design of peptides that bind specific conformers of α-synuclein","abstract":"design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a \"target backbone\" for the design of a peptide binder. Next, we interrogate structures in the PDB with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aβ40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.","journal":"Chemical Science","year":2024,"id":436440,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":889663,"name":"Hyunjun Yang","orcid":"0000-0003-2524-2201","position":1,"is_corresponding":false},{"id":586911,"name":"Sophia K. Tan","orcid":"0000-0002-6181-7810","position":2,"is_corresponding":false},{"id":584860,"name":"Henry S. Pan","orcid":"0000-0002-1323-037X","position":3,"is_corresponding":false},{"id":1244511,"name":"Rose Yang","orcid":"0000-0002-2534-0242","position":4,"is_corresponding":false},{"id":1244512,"name":"Junyi Xu","orcid":"0009-0006-0535-6892","position":5,"is_corresponding":false},{"id":733706,"name":"Hyunil Jo","orcid":"0000-0002-4863-0779","position":6,"is_corresponding":false},{"id":401479,"name":"Carlo Condello","orcid":"0000-0002-8454-5360","position":7,"is_corresponding":false},{"id":258384,"name":"Nicholas F. Polizzi","orcid":"0000-0002-1779-8907","position":8,"is_corresponding":false},{"id":239680,"name":"William F. DeGrado","orcid":"0000-0003-4745-263X","position":9,"is_corresponding":false},{"id":1244510,"name":"Hailey M. Wallace","orcid":"0000-0002-9208-3063","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:00:12.706156Z","pmid":"38846390","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":[]}