An Explicitly Solvated Full Atomistic Model of the Cardiac Thin Filament and Application on the Calcium Binding Affinity Effects from Familial Hypertrophic Cardiomyopathy Linked Mutations

Abstract

The former version of our cardiac thin filament model consisted of the troponin complex (cTn), two coiled-coil dimers of tropomyosin (Tm), and twenty-nine actin subunits. We now present the newest revision of the model to include both solvation and ionization. The model was developed to continue our study of genetic mutations in the cardiac thin filament proteins which are linked to familial hypertrophic cardiomyopathies. Binding of calcium to the cardiac troponin C subunit (cTnC) causes subtle conformational changes to propagate through the cTnC to the inhibitor subunit (cTnI) which then detaches from actin. Conformational changes propagate through to the cTnT subunit, which allow for the movement of Tm into the open position along actin. Myosin heads can bind to the seven open binding sites on actin, which upon hydrolysis of ATP leads to muscle contraction. Calcium disassociation allows for the reverse to occur, which results in muscle relaxation. Alterations in the calcium binding affinity can disrupt the natural processes of the heart. The inclusion of explicit TIP3 water solvation and an ionic concentration of 0.15 mol/L allows for the model to mimic the true conditions that the cardiac thin filament would feel. The move from implicit to explicit solvation allows us to get better individual local solvent to protein interactions; which are important when observing the N-lobe calcium binding pocket of the cTnC. We are able to compare in silica and in vitro experimental results to better understand the physiological effects from mutants, such as the R92L/W and F110V/I of the cTnT, on the calcium binding affinity compared to the wild type.