Calcium-dependent cardiac muscle contraction is regulated by the troponin protein complex (cTn), which consists of three subunits: troponin C (cTnC) the calcium binding subunit, troponin I (cTnI) which inhibits actomyosin interaction, and troponin T (cTnT) which anchors the protein complex to tropomyosin. The regulatory domain (N-terminal domain) of cTnC (cNTnC) has been a target of substantial interest for the treatment of congestive heart failure via two main approaches: computer-aided drug discovery and gene therapy. Both tactics possess great promise for treating the disease. As part of the drug discovery approach, small drug-like molecules that increase Ca<sup>2+</sup> sensitivity without altering the concentration of systolic Ca<sup>2+</sup> are of particular interest. Gene therapy has proven to be a viable approach, as previous studies have demonstrated the effectiveness of calcium sensitizing mutations to regain myocyte contractility and functionality post an induced myocardial infarction event in mouse models. We investigate the effects of altering calcium sensitization through a variety of computational approaches aimed at characterizing a potentially important new class of calcium sensitizer small molecules and measuring the between wildtype and known calcium sensitivity altering mutants of cNTnC. We utilize knowledge of known calcium sensitizers for virtual screenings of extensive chemical libraries and employ the free energy method of Adaptive Steered Molecular Dynamics (ASMD) to characterize known calcium cNTnC sensitizing and desensitizing mutations.

Measuring the calcium sensitivity of cardiac troponin C site II

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ACS Fall 2022

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