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 Ca sensitivity. Previously we showed that small molecules related to EGCG were able to restore the native response to mutant thin filaments and in MD simulations. However, 5,7-dimethoxychroman-3-yl 4-methoxybenzoate (compound ) has an opposite effect-it causes mutant thin filament Ca sensitivity to increase when cTroponin I is phosphorylated. In MD simulations of troponin with the TNNC1 G159D DCM mutation, we observed that compound 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.