{"doi":"10.7554/elife.103797.2","title":"Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments","abstract":"Abstract Small molecule ligands exhibit a diverse range of conformations in solution. Upon binding to a target protein, this conformational diversity is reduced. However, ligands can retain some degree of conformational flexibility even when bound to a receptor. In the Protein Data Bank (PDB), a small number of ligands have been modeled with distinct alternative conformations that are supported by macromolecular X-ray crystallography density maps. However, the vast majority of structural models are fit to a single ligand conformation, potentially ignoring the underlying conformational heterogeneity present in the sample. We previously developed qFit-ligand to sample diverse ligand conformations and to select a parsimonious ensemble consistent with the density. While this approach indicated that many ligands populate alternative conformations, limitations in our sampling procedures often resulted in non-physical conformations and could not model complex ligands like macrocycles. Here, we introduce several improvements to qFit-ligand, including integrating RDKit for stochastic conformational sampling. This new sampling method greatly enriches low energy conformations of small molecules and macrocycles. We further extended qFit-ligand to identify alternative conformations in PanDDA-modified density maps from high throughput X-ray fragment screening experiments, as well as single-particle cryo-electron microscopy (cryo-EM) density maps. The new version of qFit-ligand improves fit to electron density and reduces torsional strain relative to deposited single conformer models and our prior version of qFit-ligand. These advances enhance the analysis of residual conformational heterogeneity present in ligand-bound structures, which can provide important insights for the rational design of therapeutic agents.","journal":"eLife","year":2025,"id":567583,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9248,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":59239,"name":"Nathaniel Echols","orcid":null,"position":1,"is_corresponding":false},{"id":552145,"name":"G.J. Correy","orcid":"0000-0001-5155-7325","position":2,"is_corresponding":false},{"id":1338254,"name":"Priya Jaishankar","orcid":null,"position":3,"is_corresponding":false},{"id":1012419,"name":"Takaya Togo","orcid":"0000-0003-0243-0760","position":4,"is_corresponding":false},{"id":490827,"name":"Adam R. Renslo","orcid":"0000-0002-1240-2846","position":5,"is_corresponding":false},{"id":352900,"name":"Henry van den Bedem","orcid":"0000-0003-2358-841X","position":6,"is_corresponding":false},{"id":63530,"name":"James S. Fraser","orcid":"0000-0002-5080-2859","position":7,"is_corresponding":false},{"id":103672,"name":"Stephanie A. Wankowicz","orcid":"0000-0002-4225-7459","position":8,"is_corresponding":false},{"id":1042629,"name":"Jessica Flowers","orcid":"0000-0002-3501-8804","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:56:44.340853Z","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":[]}