Hypertrophic cardiomyopathy is the most common inherited heart diseases associated with a large number of mutations in several sarcomere proteins that regulate striated muscle contraction. The 3-dimensional structural and biophysical consequences of these mutations and their impact on the genotype-phenotype relationship remains poorly understood. Mutations in cardiac TroponinT (cTnT) have been reported to purport an increased risk of sudden cardiac deaths. Mutational hotspots such as codon 102 (Arg92 Moolman et al., 1997) of cTnT have been observed in several populations, including recently by our group in Egypt. In an attempt to explain this observation, we have performed molecular modelling of specific key mutations at codon 102, Arg102. The X-ray structure of the core domain of human cardiac troponin complex (cTnC, cTnI and cTnT) has been used for this study after constructing the missing regions. The resultant structure and the mutants were subjected to structural rigidity analysis and mutational modelling. In addition, molecular dynamics simulations were performed to understand the binding of functionally important calcium ions with the troponin complex. Our results suggest that the location of Arg102 in cTnT is instrumental to create a molecular bridge through hydrogen bonds (Figure) between secondary structural elements, in order to hold the core structure together. The loss of this molecular bridge by the key mutations (such as Arg102Leu) could produce conformational changes and affect natural binding of calcium ions, which are essential for regulation of muscle functions. This mechanism can explain the important structural consequences of mutations in this codon, associated with frequent progression of LV dysfunction, as well as the occurrence of ventricular arrhythmias secondary to the intracellular consequences of profound energetic and Ca++ handling derangement.


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