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Cited by 6Protein Structure and DynamicsComputational Drug Discovery MethodsReceptor Mechanisms and Signaling

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Markov state modelling reveals heterogeneous drug-inhibition mechanism of Calmodulin

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Westerlund, Annie M., Sridhar, Akshay, Dahl, Leo, Andersson, Alma, Bodnar, Anna-Yaroslava, Delemotte, Lucie·2022·PLOS Computational Biology
DOI 10.1371/journal.pcbi.1010583PMC PMC9581412

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Abstract

Calmodulin (CaM) is a calcium sensor which binds and regulates a wide range of target-proteins. 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.

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Metadata

Authors
Westerlund, A. M., Sridhar, A., Dahl, L., Andersson, A., Bodnar, A.-Y., & Delemotte, L.
Affiliations
Science for Life Laboratory (SE)
Corresponding author
Delemotte, Lucie
ORCID
Venue
PLOS Computational Biology
Publisher
Public Library of Science (PLoS)
Published
2022-10-07
Volume
18
Issue
10
Pages
e1010583
ISSN
  • 1553-734X (ISSN-L)
  • 1553-7358
DOI
10.1371/journal.pcbi.1010583
PMC
PMC9581412
OpenAlex
W4303449081
Cited by
6
References
3
Citations by year
2026: 3 · 2025: 1 · 2024: 2
FWCI
0.24
Type
journal article
Language
en
Update notices
new_version (2022-10-19)
Open access
Licence
Locations
  • PLoS Computational Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Swedish e-Science Research Centre (COVID-19 transition grant)
  • HORIZON EUROPE Marie Sklodowska-Curie Actions (898762)
  • Science for Life Laboratory
  • Göran Gustafssons Stiftelser
  • Vetenskapsrådet (2018-04905, 2019-02433)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
calmodulin, trifluoperazine, Markov state models, C-terminal domain, calcium sensor, binding mode, protein conformational dynamics, calcium binding sites, hydrophobic pocket, antipsychotic drugs, adaptive sampling
MeSH terms
Binding Sites, Calcium, Calmodulin, Protein Binding, Antipsychotic Agents, Trifluoperazine

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