Abstract
A mutant troponin T of which glutamate is replaced with aspartate (Glu244Asp) is one of the causes of familial hypertrophic cardiomyopathy (HCM). Incorporation of this mutant to skinned fibers has been reported to increase calcium sensitivity as well as maximal tension (Nakaura et al. 1999). However, mechanism has not been elucidated. Therefore, we constructed a model structure of this mutant troponin by introducing the mutation to the crystal structure of human cardiac troponin (TIC complex) obtained from Protein Data Bank (ID number 1J1E). Molecular dynamics simulation on the wild and the mutant structure was carried out in water sphere at 310 K to estimate dynamic structure and search a possible mechanism for the enhanced tension development. Dynamics was calculated by the use of software Amber ver.7. Iteration was done in TIP3 water sphere with 0.001 ps time step in non periodic condition at constant temperature (310 K). It was found that 600-ps run closed N and C termini of H1-H2 fragment of troponin I to narrower separation in mutant structure than in wild one. This conformational change of troponin I would correspond to a decrease in the distance between H3 region of troponin I and its binding site on the regulatory domain of troponin C so as to accelerate their binding which is considered to activate actomyosin interaction (Takeda et al., 2003). This may explain, at least partly, the enhanced tension development in the mutant myofilament. [Jpn J Physiol 55 Suppl:S122 (2005)]
