Abstract
Many of the troponin mutants which can cause familial cardiomyopathy have been reported so far. To elucidate the molecular mechanism of the cardiomyopathy related to troponin, we performed molecular dynamics study on the structure of troponin mutants which relate to familial hypertrophic cardiomyopathy (HCM). Two different troponin T mutant which relate to HCM, Glu244Asp and Lys247Arg were studied. Dynamics was calculated by the use of software Amber (vers. 9). Iteration was done in TIP3 water sphere with 0.5 or 1 fs time step in periodic condition at constant temperature (310 K) and pressure. Model structures of troponin mutants were constructed by introducing the mutation to the crystal structure of human cardiac troponin (core region of TIC complex) obtained from Protein Data Bank (ID number 1J1E). More than 4 trajectories of 1ns were obtained for wild and mutant structure. It was observed that electrostatic interaction between troponin I and troponin T which linked alfa helix of troponin T and troponin I in the wild was lost in the mutant. Furthermore, when a terminal residue of troponin I was pulled toward an actin molecule mimicking the intra-molecular force on activation, different structural change was observed in mutant compared with wild. The involvement of this difference between the wild and mutant in the tension regulation will be discussed. [J Physiol Sci. 2007;57 Suppl:S93]
