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This implicitly enables the concentration of calcium to influence many downstream physiological responses, including muscle contraction, learning and depression. The antipsychotic drug trifluoperazine (TFP) is a known CaM inhibitor. By binding to various sites, TFP prevents CaM from associating to target-proteins. However, the molecular and state-dependent mechanisms behind CaM inhibition by drugs such as TFP are largely unknown. Here, we build a Markov state model (MSM) from adaptively sampled molecular dynamics simulations and reveal the structural and dynamical features behind the inhibitory mechanism of TFP-binding to the C-terminal domain of CaM. We specifically identify three major TFP binding-modes from the MSM macrostates, and distinguish their effect on CaM conformation by using a systematic analysis protocol based on biophysical descriptors and tools from machine learning. The results show that depending on the binding orientation, TFP effectively stabilizes features of the calcium-unbound CaM, either affecting the CaM hydrophobic binding pocket, the calcium binding sites or the secondary structure content in the bound domain. The conclusions drawn from this work may in the future serve to formulate a complete model of pharmacological modulation of CaM, which furthers our understanding of how these drugs affect signaling pathways as well as associated diseases.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010583","type":"journal-article","created":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T13:44:00Z","timestamp":1665150240000},"page":"e1010583","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Markov state modelling reveals heterogeneous drug-inhibition mechanism of Calmodulin"],"prefix":"10.1371","volume":"18","author":[{"given":"Annie M.","family":"Westerlund","sequence":"first","affiliation":[]},{"given":"Akshay","family":"Sridhar","sequence":"additional","affiliation":[]},{"given":"Leo","family":"Dahl","sequence":"additional","affiliation":[]},{"given":"Alma","family":"Andersson","sequence":"additional","affiliation":[]},{"given":"Anna-Yaroslava","family":"Bodnar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0828-3899","authenticated-orcid":true,"given":"Lucie","family":"Delemotte","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,10,7]]},"reference":[{"key":"pcbi.1010583.ref001","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"M Kanehisa","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010583.ref002","article-title":"Calcium signalling: Dynamics, homeostasis and remodelling","author":"MJ Berridge","year":"2003","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"pcbi.1010583.ref003","article-title":"Structural diversity of calmodulin binding to its target sites","author":"H Tidow","year":"2013","journal-title":"FEBS Journal"},{"key":"pcbi.1010583.ref004","first-page":"296","article-title":"Ca2+-saturated calmodulin binds tightly to the N-terminal domain of A-type fibroblast growth factor homologous factors","author":"R Mahling","year":"2021","journal-title":"Journal of Biological Chemistry"},{"key":"pcbi.1010583.ref005","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1006072","article-title":"Effect of Ca2+on the promiscuous target-protein binding of calmodulin","volume":"14","author":"AM Westerlund","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010583.ref006","article-title":"Retention of conformational entropy upon calmodulin binding to target peptides is driven by transient salt bridges","volume":"103","author":"DMA Smith","year":"2012","journal-title":"Biophys J"},{"key":"pcbi.1010583.ref007","article-title":"The ever changing moods of calmodulin: How structural plasticity entails transductional adaptability","author":"A Villarroel","year":"2014","journal-title":"Journal of Molecular Biology"},{"key":"pcbi.1010583.ref008","first-page":"228","article-title":"Calmodulin structure refined at 1.7 \u00c5 resolution","author":"R Chattopadhyaya","year":"1992","journal-title":"J Mol Biol"},{"key":"pcbi.1010583.ref009","article-title":"Solution structure of calcium-free calmodulin","volume":"2","author":"H Kuboniwa","year":"1995","journal-title":"Nat Struct Biol"},{"key":"pcbi.1010583.ref010","doi-asserted-by":"crossref","DOI":"10.1016\/S0021-9258(18)92938-8","article-title":"Calcium binding to calmodulin and its globular domains","volume":"266","author":"S Linse","year":"1991","journal-title":"Journal of Biological Chemistry"},{"key":"pcbi.1010583.ref011","doi-asserted-by":"crossref","DOI":"10.1016\/0014-5793(95)00504-3","article-title":"NMR studies of the methionine methyl groups in calmodulin","volume":"366","author":"K Siivari","year":"1995","journal-title":"FEBS Lett"},{"key":"pcbi.1010583.ref012","article-title":"The effects of chemical modification of calmodulin on Ca2+-induced exposure of a hydrophobic region. 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