期刊
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
卷 18, 期 30, 页码 20691-20707出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c6cp02610a
关键词
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资金
- la Caixa'' Foundation within Fellowship Program for advanced studies and research in Europe
- British Heart Foundation [RG/11/20/29266, FS/12/24/29568]
- Institute of Chemical Biology of Imperial College London
- Engineering and Physical Sciences Research Council (EPSRC), UK
- British Heart Foundation [RG/11/20/29266, FS/12/24/29568] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [1647992] Funding Source: researchfish
The only available crystal structure of the human cardiac troponin molecule (cTn) in the Ca2+ 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 mu s) and bisphosphorylated (SP23/SP24) cTn (9 mu s) 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 angstrom 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 Ca2+ by stabilizing out-of-coordination distances of the cTnC's EF hand II residues, and in particular Ser 69.
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