Key result
Molecular dynamics simulations of human cardiac troponin suggest that bis-phosphorylation does not increase fluctuations but may provoke Ca(2+) loss by stabilizing out-of-coordination distances.
Molecular dynamics simulations suggest that bis-phosphorylation of cardiac troponin I may reduce calcium affinity by altering the coordination distances in the EF hand II of troponin C.
No clinical changes indicated from troponin simulations; leaves open mechanistic roles for bis-phosphorylation in Ca2+ affinity.
The only available crystal structure of the human cardiac troponin molecule (cTn) in the Ca(2+) activated state does not include crucial segments, including the N-terminus of the cTn inhibitory subunit (cTnI). We have applied all-atom molecular dynamics (MD) simulations to study the structure and dynamics of cTn, both in the unphosphorylated and bis-phosphorylated states at Ser23/Ser24 of cTnI. We performed multiple microsecond MD simulations of wild type (WT) cTn (6, 5 μs) and bisphosphorylated (SP23/SP24) cTn (9 μs) on a 419 amino acid cTn model containing human sequence cTnC (1-161), cTnI (1-171) and cTnT (212-298), including residues not present in the crystal structure. We have compared our results to previous computational studies, and proven that longer simulations and a water box of at least 25 Å are needed to sample the interesting conformational shifts both in the native and bis-phosphorylated states. As a consequence of the introduction into the model of the C-terminus of cTnT that was missing in previous studies, cTnC-cTnI interactions that are responsible for the cTn dynamics are altered. We have also shown that phosphorylation does not increase cTn fluctuations, and its effects on the protein-protein interaction profiles cannot be assessed in a significant way. Finally, we propose that phosphorylation could provoke a loss of Ca(2+) by stabilizing out-of-coordination distances of the cTnC's EF hand II residues, and in particular Ser 69.
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Zamora et al. (2016) studied Cardiac troponin structure and dynamics. Bis-phosphorylation at Ser23/Ser24 of cTnI vs. Unphosphorylated wild type cTn was evaluated on Conformational shifts and protein-protein interactions. Molecular dynamics simulations of human cardiac troponin suggest that bis-phosphorylation does not increase fluctuations but may provoke Ca(2+) loss by stabilizing out-of-coordination distances.
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