http://orcid.org/0000-0003-3817-2329
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Abstract
Phosphorylation of protein is critical for various cell processes, which preferentially happens in intrinsically disordered proteins (IDPs). How phosphorylation modulates structural ensemble of disordered peptide remains largely unexplored. Here, using replica exchange molecular dynamics (REMD) and Markov state model (MSM), the conformational distribution and kinetics of p53 N-terminal transactivation domain (TAD) 2 as well as its dual-site phosphorylated form (pSer46, pThr55) were simulated. It reveals that the dual phosphorylation does not change overall size and secondary structure element fraction, while a change in the distribution of hydrogen bonds induces slightly more pre-existing bound helical conformations. MSM analysis indicates that the dual phosphorylation accelerates conformation exchange between disordered and order-like states in target-binding region. It suggests that p53 TAD2 after phosphorylation would be more apt to bind to both the human p62 pleckstrin homology (PH) domain and the yeast tfb1 PH domain through different binding mechanism, where experimentally it exhibits an extended and α-helix conformation, respectively, with increased binding strength in both complexes. Our study implies except binding interface, both conformation ensemble and kinetics should be considered for the effects of phosphorylation on IDPs.
| Abbreviations | ||
| IDPs | = | intrinsically disordered proteins |
| REMD | = | replica exchange molecular dynamics |
| MSM | = | Markov state model |
| TAD | = | transactivation domain |
| PH | = | pleckstrin homology |
| PRR | = | proline-rich region |
| DBD | = | DNA-binding domain |
| TET | = | Tetramerization domain |
| REG | = | regulatory domain |
| MD | = | molecular dynamics |
| PME | = | particle-mesh Ewald |
| TICA | = | time-lagged independent component analysis |
| CK | = | Chapman–Kolmogorov |
| GMRQ | = | generalized matrix Rayleigh quotient |
| SARW | = | self-avoiding random walk |
| KID | = | kinase-inducible domain |
| MFPT | = | mean first passage time |
| DSSP | = | definition of secondary structure of proteins |
| RMSD | = | root mean square deviation |
| Rg | = | radius of gyration |
| Ree | = | end to end distance |
Communicated by Ramaswamy H. Sarma
Acknowledgements
We thank Prof. Luhua Lai and Prof. Yifei Qi for their helpful discussion.
Disclosure statement
No potential conflict of interest was reported by the authors.