Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants—Genotype to Cellular Phenotype

Figure 1. DCM associated mutations shown in regulatory thin filament proteins cTn and Tm. DCM mutations for cTn are shown in the cartoon representing primary amino acid sequence of cTnC, cTnI, and cTnT and in the cTnC crystal structure of the 52 kDa domain of human cTn (PDB ID—1J1E) in the calcium saturated form (cTnC in blue, cTnI in red, cTnT in orange, calcium in green, mutations in pink). Residues 1–182 are missing in the crystal structure of cTnT—the mutations in that region have been enclosed within an open box and point to a cartoon rendering of residues 1–182 of cTnT (faded orange ribbon structure juxtaposing Tm). DCM mutations in Tm are shown in crystal structure for Tm (PDB ID—1C1G) (Tm in teal, mutations in pink).

Figure 2. Schematic showing incorporation of molecular data of cTnC activation obtained from BD and MD simulations into a six-state Markov model of myofilament activation at steady-state conditions, as an example of bridging molecular to cellular scales in a modeling study by Dewan et al. (2016).

Figure 3. Schematic illustrating the scope of multi-scale modeling techniques, panning spatial and temporal scales, to complement experimental data at all biological scales. Representative examples of modeling frameworks from molecular to cellular (solid black arrow—focus of this review) to whole heart level (dotted black arrow) and growth modeling (dotted gray arrow) are shown.