{"doi":"10.1101/2023.09.14.557821","title":"Sensitivity and Frequency Response of Biochemical Cascades","abstract":"Signal transduction from a cell's surface to cytoplasmic and nuclear targets takes place through a complex network of interconnected pathways. Phosphorylation cycles are common components of many pathways and may take the form of a multi-layered cascade of cycles or incorporate species with multiple phosphorylation sites that effectively create a sequence of cycles with increasing states of phosphorylation. This work focuses on the frequency response and sensitivity of such systems, two properties that have not been thoroughly examined. Starting with a singularly phosphorylated single-cycle system, we compare the sensitivity to perturbation at steady-state across a range of input signal strengths. This is followed by a frequency response analysis focusing on the gain and associated bandwidth. Next, we consider a two-layer cascade of single phosphorylation cycles and focus on how the two cycles interact to produce various effects on the bandwidth and damping properties. Then we consider the (ultra)sensitivity of a doubly phosphorylated system, where we describe in detail first-order ultrasensitivity, a unique property of these systems, which can be blended with zero-order ultrasensitivity to create systems with relatively constant gain over a range of signal input. Finally, we give an in-depth analysis of the sensitivity of an n-phosphorylated system.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":411547,"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":0.9622,"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":60845,"name":"Joseph L. Hellerstein","orcid":"0000-0003-0802-4069","position":1,"is_corresponding":false},{"id":60883,"name":"Herbert M Sauro","orcid":"0000-0002-3659-6817","position":2,"is_corresponding":false},{"id":579348,"name":"Michael A. Kochen","orcid":"0000-0002-3379-1529","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T01:21:42.971455Z","pmid":"37781602","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":[]}