The phosphorylation of serines 22 and 23 of troponin I in cardiac troponin modulates the myofilbrillar Ca 2+ -sensitivity and increases the rate of Ca 2+ release from troponin C. It is a major determinant of the lusitropic response to adrenergic stimulation. The molecular mechanism of this process has remained unknown long after the mechanism of the troponin Ca 2+ switch itself was defined . Investigation of this subtle process at the atomic level poses a challenge for structural biology since the change in Ca 2+ -sensitivity is only about 2-fold and key parts of the troponin modulation and regulation system are disordered and cannot be fully resolved by most methodologies. In this study we have used molecular dynamics simulations of the cardiac troponin core to understand the molecular mechanism by which phosphorylation of serines 22 and 23 and a DCM linked mutation, cTnC G159D, modulate Ca 2+ regulation in cardiac muscle.