Molecular Structure, Binding Affinity, and Biological Activity in the Epigenome

Abstract

Development of valid structure–activity relationships (SARs) is a key to the elucidation of pathomechanisms of epigenetic diseases and the development of efficient, new drugs. The present review is based on selected methodologies and applications supplying molecular structure, binding affinity and biological activity data for the development of new SARs. An emphasis is placed on emerging trends and permanent challenges of new discoveries of SARs in the context of proteins as epigenetic drug targets. The review gives a brief overview and classification of the molecular background of epigenetic changes, and surveys both experimental and theoretical approaches in the field. Besides the results of sophisticated, cutting edge techniques such as cryo-electron microscopy, protein crystallography, and isothermal titration calorimetry, examples of frequently used assays and fast screening techniques are also selected. The review features how different experimental methods and theoretical approaches complement each other and result in valid SARs of the epigenome.

The Structural Effects of Phosphorylation of Protein Arginine Methyltransferase 5 on Its Binding to Histone H4

“…Although the number of experimental human PRMT5 complexes increased recently due to its importance in cancer therapy, only one structure (PDB code: 4gqb, [ 17 ]) contains an eight-amino-acid-long N-terminal peptide fragment of histone H4 bound to the catalytic domain of PRMT5. The experimental determination of a full-length histone structure may be challenging, partly due to the high flexibility of the N-terminal tail [ 4 ]. However, the catalytic domain is positioned far from T80 in space, and therefore, the PRMT5-bound structure of N-terminal tail of histone H4 alone did not provide a sufficient basis for an explanation of the effects of T80 phosphorylation.…”

“…Post-translational modification (PTM) is a fundamental mechanism occurring on proteins of different roles in epigenetic regulation [ 1 , 2 , 3 , 4 ]. Histone H4 is a building block of the nucleosome, the smallest unit of the chromosome [ 5 ].…”

Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1

“…The amino acids of a chain do not interfere with the binding of the ligand to another chain. The missing atoms and residues [43] were rebuilt using SWISS MODEL [44], and energy minimized with GROMACS [45]. The convergence threshold of the steepest descent optimization was set to 10 3 kJ mol −1 nm −1 , and that of the conjugate gra-dient optimization to 10 kJ mol −1 nm −1 .…”

Construction of Histone–Protein Complex Structures by Peptide Growing

“…Histones have a diverse interaction profile [ 1 ] and play a key role in epigenetic regulation via interactions with the DNA in the chromatin [ 2 , 3 ], as well as various protein partners [ 4 , 5 ]. Readers are important proteins that distinguish between the combinatorial numbers of post-translationally modified histone molecules commonly called as the “histone code” [ 6 ].…”

“…Thus, the binding of the N-terminal tail of histone H3 with DNA may compete with the binding of histone N-terminal tails to histone reader proteins [ 29 ], which is further supported by the increased accessibility of histone H3 during nucleosome disassembly during transcription [ 30 ]. Like all peptides, histones are also extensively hydrated, which further complicates the determination of their interactions [ 5 , 31 ]. Moreover, there are shallow binding pockets on the reader side that result in the histone–reader complexes possessing moderate stability [ 32 , 33 ], with micromolar binding constants (see K d values in Table S1 for examples).…”