Cardiac troponin C (cTnC) is the regulatory protein that initiates cardiac contraction in response to Ca2+. TnC binding Ca2+ initiates a cascade of protein-protein interactions that begins with the opening of the N-terminal domain of cTnC, followed by cTnC binding the Troponin I switch peptide (TnISW). We have evaluated, through isothermal titration calorimetry (ITC) and MD simulation, the effect of several clinically relevant mutations (A8V, L29Q, A31S, L48Q, Q50R and C84Y) on the Ca2+ affinity, structural dynamics, and calculated interaction strengths between cTnC and each of Ca2+ and TnISW. Surprisingly the Ca2+ affinity measured by ITC was only significantly affected by half of these mutations, with the exceptions of the L48Q, Q50R and C84Y mutants, which had an affinity 10-fold, 3-fold and 3-fold higher than wild-type, respectively. This suggests that Ca2+ affinity of N-TnC in isolation is insufficient to explain the pathogenicity of these mutations. Molecular Dynamics (MD) simulation was used to evaluate the effects of these mutations on Ca2+ binding, structural dynamics, and TnI interaction independently. Many of the mutations had a pronounced effect on the balance between the open and closed conformations of the TnC molecule, which provides an indirect mechanism for their pathogenic properties. Our data demonstrate that the structural dynamics of the cTnC molecule are key in determining myofilament Ca2+ sensitivity. Our data further suggest that modulation of the structural dynamics is the underlying molecular mechanism for many disease mutations that are far from the regulatory Ca2+ binding site of cTnC.
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