{"doi":"10.1101/2020.02.09.940676","title":"Differences in the free energies between the excited states of A <i>β</i> 40 and A <i>β</i> 42 monomers encode their distinct aggregation propensities","abstract":"The early events in the aggregation of the intrinsically disordered peptide, A β , involve transitions from the disordered lowest free energy ground state to assembly-competent states. Are the finger-prints of order found in the amyloid fibrils encoded in the conformations that the monomers access at equilibrium? If so, could the enhanced aggregation rate of A β 42 compared to A β 40 be rationalized from the sparsely populated high free energy states of the monomers? Here, we answer these questions in the affirmative using coarse-grained simulations of the SOP-IDP model of A β 40 and A β 42. Although both the peptides have practically identical ensemble-averaged properties, characteristic of random coils (RCs), the conformational ensembles of the two monomers exhibit sequence-specific heterogeneity. Hierarchical clustering of conformations reveals that both the peptides populate high free energy aggregation-prone ( N *) states, which resemble the monomers in the fibril structure. The free energy gap between the ground (RC) and the N * states of A β 42 peptide is smaller than for A β 40. By relating the populations of excited states of the two peptides to the fibril formation time scales using an empirical formula, we explain nearly quantitatively the faster aggregation rate of A β 42 relative to A β 40. The N * concept accounts for fibril polymorphs, leading to the prediction that the less stable N * state of A β 42, encoding for the U-bend fibril, should form earlier than the structure with the S-bend topology, which is in accord with the Ostwald’s rule rationalizing crystal polymorph formation. Significance Statement Alzheimer’s disease (AD), a rampant neurodegenerative disorder, is caused by the accumulation of pathological aggregates, primarily composed of the two isoforms A β 40 and A β 42. Experiments have shown that A β 42 is more aggregation-prone compared to A β 40. However, the molecular origin of this apparent anomaly remains elusive. Here, we provide a microscopic basis for the different aggregation rates in terms of the distinct populations of high free energy excited fibril-like states (N*) that are encoded in the monomer spectra. The N* theory explains the emergence of fibril polymorphs, and predicts the relative kinetic stabilities of A β 42 fibrils using Ostwald’s rule of stages. Our work shows that sequence-specific conformational heterogeneity of the monomer ensembles provides important cues for understanding protein aggregation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122574,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9395,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":56696,"name":"John E. Straub","orcid":"0000-0002-2355-3316","position":1,"is_corresponding":false},{"id":305612,"name":"D. Thirumalai","orcid":"0000-0003-1801-5924","position":2,"is_corresponding":false},{"id":305611,"name":"Debayan Chakraborty","orcid":"0000-0003-4339-5818","position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-18T23:14:55.385653Z","pmid":null,"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":[]}