We have used Molecular Dynamics simulations to examine structural differences of cardiac alpha and beta myosin isoforms, potentially leading to their differences in kinetics. Cardiac myosin isoforms are intensively studied due to correlation between elevated expression level of slower beta isoform and the heart failure. Relationship between kinetic properties of specific isoform and the heart function leads to the new strategy in the failing cardiac muscle treatment, direct myosin activation. Considering myosin head as the potential drug target, it is important to know how different structural elements of the molecule regulate its kinetics.Loop2 (25k-50k loop) connects two domains in myosin heavy chain subfragment S1. Studies of chimeric proteins with interchanged Loop2 showed modulation of protein kinetics and in vitro motility. It was speculated that the major affecter of myosin kinetics is the length of the Loop 2. We have constructed models of alpha and beta cardiac S1 isoforms using available X-ray structure of beta isoform and homology modeling. Trajectories of 0.5us length in explicit solvent for each isoform were calculated. Conformational analysis revealed several regions (including Loop2), adopting significantly different conformations amongst alpha and beta isoforms. The terminal regions of Loop2 in alpha myosin undergo coil-to-helix transitions. This process correlates with the breakdown of salt bridges, coupling Loop2 to the 7-stranded beta sheet in the core of myosin. In contrast, these salt bridges are conserved in the beta myosin isoform. Loop2 is connected to helices attached to P-loop and switch II loop within myosin active site. We conclude that observed coil-to-helix transition within Loop2 of alpha cardiac myosin decouples structural elements of the active site and the 7-stranded beta sheet, thus modulating kinetics of ATP hydrolysis and ADP release. Supported by NIH AR59621.