5,7-Dimethoxychroman-3-yl 4-methoxybenzoate Has a Unique Effect upon the Modulation of Mutant Cardiac Muscle Thin Filament Function and Dynamics due to Phosphorylation of Troponin I

Mutations in thin filament proteins that cause cardiomyopathy commonly cause an uncoupling of the relationship between the phosphorylation of troponin I and reduced Ca²⁺ sensitivity. Previously we showed that small molecules related to EGCG were able to restore the native response to mutant thin filaments <i>in vitro</i> and in MD simulations. However, 5,7-dimethoxychroman-3-yl 4-methoxybenzoate (compound <b>7</b>) has an opposite effect-it causes mutant thin filament Ca²⁺ sensitivity to increase when cTroponin I is phosphorylated. In MD simulations of troponin with the TNNC1 G159D DCM mutation, we observed that compound <b>7</b> has unique effects upon troponin dynamics. Global parameters, such as interdomain hinge angle and Troponin C helix A/B angle distributions tend to be independent of phosphorylation unlike the phosphorylation-dependent changes observed with G159D alone or G159D plus recouplers such as silybin B. CCPTraj and Cluster Analysis suggest a novel preferred binding region between the extreme N terminus of cTroponin C and the switch peptide of cTroponin I.