{"doi":"10.1016/j.bpj.2025.09.007","title":"Many will enter, few will win: Cost and sensitivity of exploratory dynamics","abstract":"A variety of biomolecular systems rely on exploratory dynamics to reach target locations or states within a cell. Without a mechanism to remotely sense and move directly toward a target, the system must sample over many paths, often including resetting transitions back to the origin. We investigate how exploratory dynamics can confer an important functional benefit: the ability to respond to small changes in parameters with large shifts in the steady-state behavior. However, such enhanced sensitivity comes at a cost: resetting cycles require energy dissipation to push the system out of its equilibrium steady state. We focus on minimalist models for two concrete examples: translational proofreading in the ribosome and microtubule length control via dynamic instability to illustrate the trade-offs between energetic cost and sensitivity. In the former, a driven hydrolysis step enhances the ability to distinguish between substrates and decoys with small binding energy differences. In the latter, resetting cycles enable catalytic control, with the steady-state length distribution modulated by substoichiometric concentrations of a reusable catalyst. Synthesizing past models of these well-studied systems, we show how path-counting and circuit-mapping approaches can be used to address fundamental questions such as the number of futile cycles inherent in translation and the steady-state length distribution of a dynamically unstable polymer. In both cases, a limited amount of thermodynamic driving is sufficient to yield a qualitative transition to a system with enhanced sensitivity, enabling accurate discrimination and catalytic control at a modest energetic cost.","journal":"Biophysical Journal","year":2025,"id":546695,"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":0.9487,"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":444015,"name":"Milo M. Lin","orcid":"0000-0001-8680-2685","position":1,"is_corresponding":false},{"id":96741,"name":"Rob Phillips","orcid":"0000-0003-3082-2809","position":2,"is_corresponding":false},{"id":449527,"name":"Elena F. Koslover","orcid":"0000-0003-4139-9209","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:53:36.567932Z","pmid":"40909154","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":[]}