Abstract
Histone tails are the short peptide protrusions outside of the nucleosome core particle and they play a critical role in regulating chromatin dynamics and gene activity. A histone H3 N-terminal tail, like other histone tails, can be covalently modified on different residues to activate or repress gene expression. Previous studies have indicated that, despite its intrinsically disordered nature, the histone H3 N-terminal tail has regions of notable secondary structural propensities. To further understand the structure-dynamics-function relationship in this system, we have carried out 75.6 μs long implicit solvent simulations and 29.3 μs long explicit solvent simulations. The extensive samplings allow us to better characterize not only the underlying free energy landscape but also kinetic properties through Markov state models (MSM). Dihedral principal component analysis (dPCA) and locally scaled diffusion map (LSDMap) analysis yield consistent results that indicate an overall flat free energy surface with several shallow basins that correspond to conformations with a high α-helical propensity in two regions of the peptide. Kinetic information extracted from Markov state models reveals rapid transitions between different metastable states with mean first passage times spanning from several hundreds of nanoseconds to hundreds of microseconds. These findings shed light on how the dynamical nature of the histone H3 N-terminal tail is related to its function. The complementary nature of dPCA, LSDMap and MSM for the analysis of biomolecules is also discussed.
Highlights
In eukaryotic cells, highly conserved histone proteins provide the basic scaffold to package the genome inside the nucleus, while playing a critical role in regulating gene activity at the same time
We characterize the free energy landscape by analyzing the conformational features of macro states from Markov state models (MSM) and comparing the observations to the free energy surface computed by Dihedral principal component analysis (dPCA) and locally scaled diffusion map (LSDMap)
To evaluate the convergence of the simulations, we monitor the radius of gyration (Rg) distribution and the dPCA free energy surface when only part of the simulation data is used
Summary
Highly conserved histone proteins provide the basic scaffold to package the genome inside the nucleus, while playing a critical role in regulating gene activity at the same time. Methylation of the K4 residue is linked to gene activation while methylation of K9 or K27 is linked to gene repression.[14,15,16] Methylation of K9 is a specific target for heterochromatin protein 1 (HP1).[15,17,18] In the NMR structure of its complex with HP1, the region from K4 to S10 showed an extended structure with K4 and K9 both in the dimethylated form.[19] In another study, an 8-residue variant of the peptide with trimethylated K4 showed an extended b-strand conformation from A1 to T6 in complex
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