Abstract
Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation with the N-terminal peptide tails of histones. Determination of structures of histone-reader complexes would be a key to unravel the histone code and the design of new drugs. However, the large number of possible histone complex variations imposes a true challenge for experimental structure determination techniques. Calculation of such complexes is difficult due to considerable size and flexibility of peptides and the shallow binding surfaces of the readers. Moreover, location of the binding sites is often unknown, which requires a blind docking search over the entire surface of the target protein. To accelerate the work in this field, a new approach is presented for prediction of the structure of histone H3 peptide tails docked to their targets. Using a fragmenting protocol and a systematic blind docking method, a collection of well-positioned fragments of the H3 peptide is produced. After linking the fragments, reconstitution of anchoring regions of the target-bound H3 peptide conformations was possible. As a first attempt of combination of blind and fragment docking approaches, our new method is named fragment blind docking (FBD).
Highlights
IntroductionEpigenetics has opened up new pathways of drug discovery [1]. Among epigenetic events, post-translational modifications (PTM) of histone proteins are of particular interest [2,3,4]
In the past decades, epigenetics has opened up new pathways of drug discovery [1]
The AutoDock 4.2. [25] program package was used with Lamarckian Genetic Algorithm (LGA), AutoGrid 4.2 was used for calculation of grid maps of the target molecule with pre-calculated energy values
Summary
Epigenetics has opened up new pathways of drug discovery [1]. Among epigenetic events, post-translational modifications (PTM) of histone proteins are of particular interest [2,3,4]. The N-terminal histone H3 peptide has seven locations of K (Figure 1A) and methylation can result in 47 PTM variations (four comes from the three PTMs plus the non-modified K) In this way, an enormous number of PTM variations can be derived if all above-mentioned amino acids and modifying groups are considered. This agreement with the experimental conformation was found appropriate for the linking step (Figure 2) described . Finding the C-terminal region of the H3 peptide tail was difficult in all of the test cases indifferent of the secondary structure, due to the shallow binding site and weak interaction with the target protein, as reflected by the calculated Einter and Ninter values (Figure 4), as well. In the case of our 4lk test system, where the H3 peptide tail has an α-helix secondary structure when bound to the target protein, the intramolecular hydrogen bonds in the helix made the docking even more challenging than in other test cases
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