{"doi":"10.1039/d2cp02851d","title":"Molecular insights into the oligomerization dynamics and conformations of amyloidogenic and non-amyloidogenic amylin from discrete molecular dynamics simulations","abstract":"The amyloid aggregation of human islet amyloid polypeptide (hIAPP) is associated with pancreatic β-cell death in type 2 diabetes. The S20G substitution of hIAPP (hIAPP(S20G)), found in Japanese and Chinese people, is more amyloidogenic and cytotoxic than wild-type hIAPP. Rat amylin (rIAPP) does not have aggregation propensity or cytotoxicity. Mounting evidence suggests that soluble low-molecular-weight amyloid oligomers formed during early aggregation are more cytotoxic than mature fibrils. The self-assembly dynamics and oligomeric conformations remain unknown because the oligomers are heterogeneous and transient. The molecular mechanism of sequence-variation rendering dramatically different aggregation propensity and cytotoxicity is also elusive. Here, we investigate the oligomerization dynamics and conformations of amyloidogenic hIAPP, hIAPP(S20G), and non-amyloidogenic rIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our simulation results demonstrated that all three monomeric amylin peptides mainly adopted an unstructured formation with partial dynamical helices near the N-terminus. Relatively transient β-hairpins were more abundant in hIAPP and hIAPP(S20G) than in rIAPP. The S20G-substituting mutant of hIAPP altered the turn region of the β-hairpin motif, resulting in more hydrophobic residue-pairwise contacts within the β-hairpin. Oligomerization dynamic investigation revealed that all three peptides spontaneously accumulated into helix-populated oligomers. The conformational conversion to form β-sheet-rich oligomers was only observed in hIAPP and hIAPP(S20G). The population of high-β-sheet-content oligomers was enhanced by S20G substitution. Interestingly, both hIAPP and hIAPP(S20G) could form β-barrel formations, and the β-barrel propensity of hIAPP(S20G) was three times larger than that of hIAPP. No β-sheet-rich or β-barrel formations were observed in rIAPP. Our direct observation of the correlation between β-barrel oligomer formation and cytotoxicity suggests that β-barrels might play a critically important role in the cytotoxicity of amyloidosis.","journal":"Physical Chemistry Chemical Physics","year":2022,"id":250722,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":740978,"name":"Yuying Liu","orcid":"0000-0002-9119-4925","position":1,"is_corresponding":false},{"id":892976,"name":"Yu Zhang","orcid":"0000-0001-6751-9294","position":2,"is_corresponding":false},{"id":504263,"name":"Guanghong Wei","orcid":"0000-0001-5814-3328","position":3,"is_corresponding":false},{"id":252249,"name":"Feng Ding","orcid":"0000-0003-1850-6336","position":4,"is_corresponding":false},{"id":364016,"name":"Yunxiang Sun","orcid":"0000-0001-9799-7131","position":5,"is_corresponding":false},{"id":628578,"name":"Ying Wang","orcid":"0000-0003-4524-1812","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"36098068","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":[]}