Search

Background Post-translational modifications of histones, and in particular of their disordered N-terminal tails, play a major role in epigenetic regulation. The identification of proteins and proteic domains that specifically bind modified histones is therefore of paramount importance to understand the molecular mechanisms of epigenetics. Methods We performed an energetic analysis using the MM/PBSA method in order to study known complexes between methylated histone H3 and effector domains of the PHD family. We then developed a simple molecular dynamics based predictive model based on our analysis. Results We present a thorough validation of our procedure, followed by the computational predictions of new PHD domains specific for binding histone H3 methylated on lysine 4 (K4). Conclusions PHD domains recognize methylated K4 on histone H3 in the context of a linear interaction motif (LIM) formed by the first four amino acids of histone H3 as opposed to recognition of a single methylated site. PHD domains with different sequences find chemically equivalent solutions for stabilizing the histone LIM and these can be identified from energetic analysis. This analysis, in turn, allows for the identification of new PHD domains that bind methylated H3 K4 using information that cannot be retrieved from sequence comparison alone. General significance Molecular dynamics simulations can be used to devise computational proteomics protocols that are both easy to implement and interpret, and that yield reliable predictions that compare favorably to and complement experimental proteomics methods. This article is part of a Special Issue entitled Recent developments of molecular dynamics. [ABSTRACT FROM AUTHOR]

We describe the development of force field parameters for methylated lysines and arginines, and acetylated lysine for the CHARMM all-atom force field. We also describe a CHARMM united-atom force field for modified sidechains suitable for use with fragment-based docking methods. The development of these parameters is based on results of ab initio quantum mechanics calculations of model compounds with subsequent refinement and validation by molecular mechanics and molecular dynamics simulations. The united-atom parameters are tested by fragment docking to target proteins using the MCSS procedure. The all-atom force field is validated by molecular dynamics simulations of multiple experimental structures. In both sets of calculations, the computational predictions using the force field were compared to the corresponding experimental structures. We show that the parameters yield an accurate reproduction of experimental structures. Together with the existing CHARMM force field, these parameters will enable the general modeling of post-translational modifications of histone tails. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]