A Revised Atomistic Model of the Cardiac Thin Filament and Application to a Specific Disease Causing Mutation

Abstract

We have previously proposed an atomistic model of the thin filament which includes the troponin compex (cTn) and tropomyosin (Tm). We here discuss a newly revised model which includes twenty-nine actin subunits, four Tm chains, and the three cTn subunits. In addition, this model includes a corrected region of the Tm overlap based on more recent information. We develop this model to study genetic mutations in the proteins of the cardiac thin filament which can lead to familial hypertrophic cardiomyopathies. When calcium binds to the cardiac troponin C subunit (cTnC), subtle conformational changes propagate through the cTnC to the inhibitor subunit (cTnI), which detaches from actin. The detachment along with conformational propagation through to the cTnT subunit, moves Tm into the open position on actin. When Tm is in the open position, myosin binds to the seven open binding sites on actin, which upon hydrolysis of ATP eventually leads to muscle contraction. Molecular dynamics simulations of the full atomistic model reveal the conformational changes upon calcium activation of the cTnC. Comparison of the wildtype and the Tm D230N mutation sheds light the mutational effects in the Tm overlap region. It is critical to include actin in the model when studying this region. Simulations show mutation results in increased splaying of the Tm C-terminus end in the overlap region, in accord with recent experimental results from one of our labs.