Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation-An Integrated Multiscale...

Area of Science:

• Cardiovascular Biology
• Molecular Biophysics
• Computational Biology

Background:

• Mutations in cardiac troponin C (cTnC) are linked to dilated cardiomyopathy (DCM).
• The precise molecular mechanisms underlying altered myofilament function in these mutants are not fully understood.
• Understanding these mechanisms is crucial for elucidating DCM pathogenesis.

Purpose of the Study:

• To investigate the in silico intramolecular mechanisms by which cTnC mutations (D75Y, E59D, G159D) affect myofilament contraction.
• To test the hypothesis that intramolecular effects explain altered calcium sensitivity for D75Y and E59D mutations.
• To determine if altered cTnC-cTnI interaction contributes to the G159D mutation's effects.

Main Methods:

• Employed a multiscale approach combining molecular dynamics (MD) and Brownian dynamics (BD) simulations.
• Estimated cTnC calcium association and hydrophobic patch opening rates.
• Integrated simulation parameters into a Markov model of myofilament activation to compute force-pCa relationships.

Main Results:

• D75Y and E59D mutations' effects on myofilament calcium sensitivity can be explained by altered calcium binding affinity and hydrophobic patch opening rates.
• A partial cTnC interhelical opening angle (110°) appears sufficient for cTnI switch peptide association with D75Y and E59D.
• Contractile alterations due to G159D require accounting for interactions between cTnC and cTnI within the cardiac troponin complex.

Conclusions:

• This study provides the first multiscale in silico elucidation of how cTnC mutations translate to altered myofilament contractile function.
• Distinct molecular mechanisms underlie the contractile dysfunction caused by different cTnC mutations.
• Findings offer a deeper understanding of the molecular basis of DCM linked to cTnC mutations.