Markov state modelling reveals heterogeneous drug-inhibition mechanism of Calmodulin

• DOI: 10.1371/journal.pcbi.1010583
• Publication Date: 2022-10-07T17:44:00Z
• Authors: Annie M. Westerlund; Akshay Sridhar; Leo Dahl; Alma Andersson; Anna-Yaroslava Bo...; Lucie Delemotte
• Keywords: Trifluoperazine; Calcium Signaling

Calmodulin (CaM) is a calcium sensor which binds and regulates wide range of target-proteins. This implicitly enables the concentration to influence many downstream physiological responses, including muscle contraction, learning depression. The antipsychotic drug trifluoperazine (TFP) known CaM inhibitor. By binding various sites, TFP prevents from associating However, molecular state-dependent mechanisms behind inhibition by drugs such as are largely unknown. Here, we build Markov state model (MSM) adaptively sampled dynamics simulations reveal structural dynamical features inhibitory mechanism TFP-binding C-terminal domain CaM. We specifically identify three major binding-modes MSM macrostates, distinguish their effect on conformation using systematic analysis protocol based biophysical descriptors tools machine learning. results show that depending orientation, effectively stabilizes calcium-unbound CaM, either affecting hydrophobic pocket, sites or secondary structure content in bound domain. conclusions drawn this work may future serve formulate complete pharmacological modulation furthers our understanding how these affect signaling pathways well associated diseases.