Intermolecular And Dynamic Investigation of The Mechanism of Action of Reldesemtiv on Fast Skeletal Muscle Troponin Complex Toward the Treatment of Impaired Muscle Function

Figures

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  Fig. 1. Structure of fast skeletal muscle troponin complex (PDB ID; 1YTZ). A shows the complex highlighting the binding pocket of small molecule activators (magenta) with Reldesemtiv docked inside. B shows the fast skeletal troponin T (sTnT) subunit (blue ribbons). C shows the fast skeletal troponin I (sTnI) subunit (green), magenta region shows the area that partakes in interactions with Reldesemtiv. D shows the fast skeletal troponin C (red) subunit with highlight on the binding site on the N-terminal (magenta). Green balls show calcium ions bound to the subunit (Color figure online)

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  Fig. 2. Structural comparison of the troponin C of 1YTZ used in this study to high resolution structures by estimating the root mean square deviations. A Shows superimposition of troponin C of 1YTZ (red) and troponin C of 5TNC (cyan) with an RMSD value of 3.79 Å. B Shows superimposition of troponin C of 1YTZ (red) and troponin C of 1TCF (yellow) with an RMSD value of 1.44 Å. C Shows superimposition of troponin C of 1YTZ (red) and troponin C of 1NCZ (green) with an RMSD value of 3.79 Å and D Shows superimposition of troponin C of 1YTZ (red) and troponin C of INCX (blue) with an RMSD value of 3.78 Å (Color figure online)

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  Fig. 3. A Comparative RMSD plots of C-α atoms of unbound fast skeletal troponin C (black) and Reldesemtiv-sTnC complex (red) showing system stability and convergence during 150 ns simulation. B Comparative RMSF plots of individual residues of unbound fast skeletal troponin C (black) and Reldesemtiv-sTnC complex (red) showing increased fluctuation of Reldesemtiv complex residues. C Comparative RoG plots of C-α atoms of unbound fast skeletal troponin C (black) and Reldesemtiv-sTnC complex (red) depicting the compactness of the systems during 150 ns simulation. D Comparative SASA plots of C-α atoms of unbound fast skeletal troponin C (black) and Reldesemtiv-sTnC complex (red) showing the reduction in solvent availability surface area of the Reldesemtiv complex (Color figure online)

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  Fig. 4. A (A1) Comparative RMSD plots of C-α atoms of unbound C-terminal of fast skeletal troponin C (black) and the C-terminal of Reldesemtiv-sTnC complex (red) showing system stability during 150 ns simulation (B1) Comparative RMSF plots of individual residues of the C-terminal of the unbound fast skeletal troponin C (black) and C-terminal of Reldesemtiv-sTnC complex (red) showing increased fluctuation of Reldesemtiv complex residues (C1) Comparative SASA plots of C-α atoms of the C-terminal of the unbound fast skeletal troponin C (black) and C-terminal of Reldesemtiv-sTnC complex (red) showing the reduction in solvent availability surface area of the Reldesemtiv complex terminal. (D1) Superimposition of the C-terminals of the of the unbound sTnC and the Reldesemtiv complex showing terminal flexibility. B Comparative RMSD plots of C-α atoms of unbound N-terminal of fast skeletal troponin C (black) and the N-terminal of Reldesemtiv-sTnC complex (red) showing system stability during 150 ns simulation (B2) Comparative RMSF plots of individual residues of the N-terminal of the unbound fast skeletal troponin C (black) and N-terminal of Reldesemtiv-sTnC complex (red) showing increased…

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  Fig. 5. Interaction trajectory of Reldesemtiv with the N-terminal and troponin I switch residues over 150 ns simulation. Snapshots at 1, 50, 100 and 150 ns shows Reldesemtiv interacts with the residues through varying interactions involving conventional and carbon hydrogen interactions, pi-alky, pi-pi, halogen, pi-sulfur and van der Waals interactions

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  Fig. 6. A Per-residue energy plots of binding sites residues towards Reldesemtiv complexing with fast skeletal troponin complex. B The 3D representation of intermolecular interactions exhibited by Reldesemtiv. C shows the plot of the RMSD of Reldesemtiv over the 150 ns simulation, graph depicts general stability within the binding pocket and D Superimposition of Reldesemtiv at 1, 50, 100 and 150 ns