Key result
In silico multiscale modeling demonstrated that D75Y and E59D cTnC mutations alter calcium binding affinity and hydrophobic patch opening, while G159D alters cTnC-cTnI interactions.
This multiscale in silico study elucidates the distinct molecular mechanisms by which specific cTnC mutations (D75Y, E59D, G159D) associated with dilated cardiomyopathy alter myofilament contractile function.
May inform mutation-specific therapies in dilated cardiomyopathy; extends mechanistic insights but leaves open clinical translation.
Mutations in cardiac troponin C (D75Y, E59D, and G159D), a key regulatory protein of myofilament contraction, have been associated with dilated cardiomyopathy (DCM). Despite reports of altered myofilament function in these mutants, the underlying molecular alterations caused by these mutations remain elusive. Here we investigate in silico the intramolecular mechanisms by which these mutations affect myofilament contraction. On the basis of the location of cardiac troponin C (cTnC) mutations, we tested the hypothesis that intramolecular effects can explain the altered myofilament calcium sensitivity of force development for D75Y and E59D cTnC, whereas altered cardiac troponin C-troponin I (cTnC-cTnI) interaction contributes to the reported contractile effects of the G159D mutation. We employed a multiscale approach combining molecular dynamics (MD) and Brownian dynamics (BD) simulations to estimate cTnC calcium association and hydrophobic patch opening. We then integrated these parameters into a Markov model of myofilament activation to compute the steady-state force-pCa relationship. The analysis showed that myofilament calcium sensitivity with D75Y and E59D can be explained by changes in calcium binding affinity of cTnC and the rate of hydrophobic patch opening, if a partial cTnC interhelical opening angle (110°) is sufficient for cTnI switch peptide association to cTnC. In contrast, interactions between cTnC and cTnI within the cardiac troponin complex must also be accounted for to explain contractile alterations due to G159D. In conclusion, this is the first multiscale in silico study to elucidate how direct molecular effects of genetic mutations in cTnC translate to altered myofilament contractile function.
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Dewan et al. (2016) studied Dilated cardiomyopathy (DCM). cTnC DCM Mutations (D75Y, E59D, and G159D) was evaluated on Myofilament calcium sensitivity and contractile function. In silico multiscale modeling demonstrated that D75Y and E59D cTnC mutations alter calcium binding affinity and hydrophobic patch opening, while G159D alters cTnC-cTnI interactions.
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