Extensive studies have been made of the mechanism of Ca 2+ regulation of contraction at the functional and structural levels but there is almost no information on the structural basis of the modulation of Ca 2+ sensitivity by TnI phosphorylation. The reason for this is that troponin is an extremely asymmetric molecule comprising three polypeptides. X-ray crystallography has defined the structure of the core of cardiac troponin only in the Ca 2+ free, unphosphorylated state, moreover most of the peptides involved in regulation are mobile and missing from these structures. The Ca 2+ switch involves the interaction of the N-terminal lobe of TnC and the C-terminal domain of TnI, that is believed to be released when Ca 2+ binds to TnC, whilst the phosphorylation-dependent modulation involves the N- terminal lobe of TnC and the N-terminal domain of TnI (Ser 23 and 24 are phosphorylated by PKA). NMR has been used to define the structure of the missing peptides and their binary complexes with TnC N-terminal lobe in several states and a 'best guess' structure was proposed by building these onto the core structure that provides a starting point for our studies. We present here our MD simulations using the AMBER force field of unphosphorylated and phosphorylated Troponin I, T and C, and show the effect of phosphorylation on the overall structure. bis-phosphorylated Cardiac Troponin

Structure of the interaction between troponin I N-terminal peptide and the N-terminal lobe of troponin C studied by molecular dynamics

248th National Meeting (2014)

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