{"doi":"10.1101/2023.03.24.534170","title":"Label-free observation of individual solution phase molecules","abstract":"Abstract The vast majority of chemistry and biology occurs in solution, and new label-free analytical techniques that can help resolve solution-phase complexity at the single-molecule level can provide new microscopic perspectives of unprecedented detail. Here, we use the increased light-molecule interactions in high-finesse fiber Fabry-Pérot microcavities to detect individual biomolecules as small as 1.2 kDa with signal-to-noise ratios >100, even as the molecules are freely diffusing in solution. Our method delivers 2D intensity and temporal profiles, enabling the distinction of sub-populations in mixed samples. Strikingly, we observe a linear relationship between passage time and molecular radius, unlocking the potential to gather crucial information about diffusion and solution-phase conformation. Furthermore, mixtures of biomolecule isomers of the same molecular weight can also be resolved. Detection is based on a novel molecular velocity filtering and dynamic thermal priming mechanism leveraging both photo-thermal bistability and Pound-Drever-Hall cavity locking. This technology holds broad potential for applications in life and chemical sciences and represents a major advancement in label-free in vitro single-molecule techniques.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398860,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1175041,"name":"Carlos Saavedra","orcid":"0000-0003-3165-9521","position":1,"is_corresponding":false},{"id":1175305,"name":"Julia K. Rasch","orcid":null,"position":2,"is_corresponding":false},{"id":1175042,"name":"Daniel Sole-Barber","orcid":"0000-0002-8814-1056","position":3,"is_corresponding":false},{"id":1175043,"name":"Beau S. Schweitzer","orcid":"0000-0001-6872-2147","position":4,"is_corresponding":false},{"id":1175044,"name":"Alex J. Fairhall","orcid":"0009-0007-5657-7027","position":5,"is_corresponding":false},{"id":1175045,"name":"Cecilia H. Vollbrecht","orcid":"0000-0002-0568-1242","position":6,"is_corresponding":false},{"id":1175306,"name":"Brandon Mehlenbacher","orcid":null,"position":7,"is_corresponding":false},{"id":1175046,"name":"Zhao Zhang","orcid":"0000-0002-9009-9045","position":8,"is_corresponding":false},{"id":1175047,"name":"Lukas Tenbrake","orcid":"0009-0003-8509-0286","position":9,"is_corresponding":false},{"id":1175048,"name":"Hannes Pfeifer","orcid":"0000-0002-1713-6102","position":10,"is_corresponding":false},{"id":299758,"name":"Edwin R. Chapman","orcid":"0000-0001-9787-8140","position":11,"is_corresponding":false},{"id":353118,"name":"Randall H. Goldsmith","orcid":"0000-0001-9083-8592","position":12,"is_corresponding":false},{"id":477303,"name":"Lisa-Maria Needham","orcid":"0000-0002-8139-5862","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T01:19:51.724387Z","pmid":"36993572","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":[]}