Exploring PHD Fingers and H3K4me0 Interactions with Molecular Dynamics Simulations and Binding Free Energy Calculations: AIRE-PHD1, a Comparative Study

Abstract

PHD fingers represent one of the largest families of epigenetic readers capable of decoding post-translationally modified or unmodified histone H3 tails. Because of their direct involvement in human pathologies they are increasingly considered as a potential therapeutic target. Several PHD/histone-peptide structures have been determined, however relatively little information is available on their dynamics. Studies aiming to characterize the dynamic and energetic determinants driving histone peptide recognition by epigenetic readers would strongly benefit from computational studies. Herein we focus on the dynamic and energetic characterization of the PHD finger subclass specialized in the recognition of histone H3 peptides unmodified in position K4 (H3K4me0). As a case study we focused on the first PHD finger of autoimmune regulator protein (AIRE-PHD1) in complex with H3K4me0. PCA analysis of the covariance matrix of free AIRE-PHD1 highlights the presence of a “flapping” movement, which is blocked in an open conformation upon binding to H3K4me0. Moreover, binding free energy calculations obtained through Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology are in good qualitative agreement with experiments and allow dissection of the energetic terms associated with native and alanine mutants of AIRE-PHD1/H3K4me0 complexes. MM/PBSA calculations have also been applied to the energetic analysis of other PHD fingers recognizing H3K4me0. In this case we observe excellent correlation between computed and experimental binding free energies. Overall calculations show that H3K4me0 recognition by PHD fingers relies on compensation of the electrostatic and polar solvation energy terms and is stabilized by non-polar interactions.

Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases

“…Indeed, a substitution of the cysteine with tyrosine predicts disruption of PHD1 folding ( Figure 3B; Chakravarty et al, 2009). Additional structural analyses revealed that many of the reported missense mutations changed amino acids that were conserved among different species (Figures 3B and S5;Bjö rses et al, 2000;Org et al, 2008;Spiliotopoulos et al, 2012) and could similarly affect the Zn 2+ -binding or folding of the domain.…”

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

“…Binding free energy calculations of AKR1B10 and reference inhibitor/hit compounds The Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method was used to compute the binding free energies of the protein-ligand complexes, as described earlier [38][39][40] . For this purpose, 20 snapshots of each complex (AKR1B10 and reference inhibitor/hit compounds) were chosen evenly from 0 to 10 ns MD trajectories according to earlier reports [38,41] .…”

Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor

“…The long-range electrostatic interactions were treated with the Particle Mesh Ewald (PME) technique while non-bond interactions were truncated with an 1.2-nm cutoff. The MM/PBSA approach was applied to binding energy calculations using GMXAPBS tool 52 , which is a Bash/Perl script to facilitate the interface between GROMACS and APBS 53 . The average of last 15 ns MD simulations (600 frames) was considered to calculate the binding energy and the entropic term was neglected.…”