The objective of this model is to investigate the mechanisms behind desensitization of thin filaments to Ca 2+ due to troponin I (TnI) Ser 23/24 phosphorylation and (-)-epigallocatechin-3-gallate (EGCG) binding. The hypothesis is that TnI phosphorylation and EGCG binding desensitize thin filaments via enhanced stabilization of protein-protein interactions within the troponin complex. AlphaFold 3 recreated de novo structural models of phosphorylated TnI bound to the troponin (Tn) complex. Molecular docking simulations modeled EGCG binding to Tn. AlphaFold 3 revealed that TnI phosphorylation increased the distancing of the TnI N terminus from the TnC N-lobe due to the formation of an α-helix at the Ser 23/24 phosphorylation sites. Molecular docking simulations localized the EGCG binding site in the Tn complex that resulted from hydrogen-bonds between EGCG and the troponin C (TnC) C-lobe (residues 120–161) as well as at the beginning of the TnI IT arm and the TnI N terminus where Ser 23/24 phosphorylation sites lie. The results suggest that EGCG and TnI Ser 23/24 phosphorylation desensitization mechanisms are potentially allosteric, with phosphorylation modifying interactions between TnI and TnC N-terminal domains and EGCG between TnI and TnC C-terminal domains. The results of this work could inform the development of more targeted therapies to treat diastolic heart diseases such as HFpEF and cardiomyopathies derived from over-sensitization of thin filaments to Ca 2+ .
Tigro et al. (Sun,) studied this question.