Abstract
The binding affinity between the histone 3 (H3) tail and the ADD domain of ATRX (ATRX ADD ) increases with the subsequent addition of methyl groups on lysine 9 on H3. To improve our understanding of how the difference in methylation state affects binding between H3 and the ATRX ADD , we adopted a metadynamic approach to explore the recognition mechanism between the two proteins and identify the key intermolecular interactions that mediate this protein-peptide interaction (PPI). The non-methylated H3 peptide is recognized only by the PHD finger of ATRX ADD while mono-, di-, and trimethylated H3 is recognized by both the PHD and GATA-like zinc finger of the domain. Furthermore, water molecules play an important role in orienting the lysine 9 anchor towards the GATA-like zinc finger, which results in stabilizing the lysine 9 binding pocket on ATRX ADD . We compared our computational results against experimentally determined NMR and X-ray structures by demonstrating the RMSD, order parameter S 2 and hydration number of the complex. The metadynamics data provide new insight into roles of water-bridges and the mechanisms through which K9 hydration stabilizes the H3K9me3:ATRX ADD PPI, providing context for the high affinity demonstrated between this protein and peptide.
Original language | English (US) |
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Pages (from-to) | 594-602 |
Number of pages | 9 |
Journal | Biochimica et Biophysica Acta - Gene Regulatory Mechanisms |
Volume | 1861 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2018 |
Externally published | Yes |
Keywords
- ADD domain of ATRX
- Free energy landscape
- Metadynamics
- Methylated histone H3
- Molecular dynamics
- Recognition mechanism
ASJC Scopus subject areas
- Biophysics
- Structural Biology
- Biochemistry
- Molecular Biology
- Genetics