Abstract
Some of the main challenges faced in drug discovery are pocket flexibility and binding mode prediction. In this work, we explored the aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction by means of in silico approaches. We first investigated the Spindlin1 aromatic cage plasticity by analyzing the available crystal structures and through molecular dynamic simulations. Then we assessed the ability of rigid docking and flexible docking to rightly reproduce the binding mode of a known ligand into Spindlin1, as an example of a reader protein displaying flexibility in the binding pocket. The ability of induced fit docking was further probed to test if the right ligand binding mode could be obtained through flexible docking regardless of the initial protein conformation. Finally, the stability of generated docking poses was verified by molecular dynamic simulations. Accurate binding mode prediction was obtained showing that the herein reported approach is a highly promising combination of in silico methods able to rightly predict the binding mode of small molecule ligands in flexible binding pockets, such as those observed in some reader proteins.
Highlights
Histone reader proteins are components of a large family of proteins that regulate epigenetic activity by binding to specific histone tails
The Spindlin1 crystal structures deposited in the Protein Data Bank (PDB) [29] were analyzed in order to investigate the conformational flexibility of the binding pocket residues
Attention was given to the second domain and to the aromatic cage residues (Phe141, Trp151, Tyr170, Tyr177) as it is responsible for the recognition of the trimethylated lysine and mimetic moieties like the positively charged pyrrolidine
Summary
Histone reader proteins are components of a large family of proteins that regulate epigenetic activity by binding to specific histone tails. Spindlin is a chromatin reader protein that comprises three Tudor domains and it is known to recognize two different histone marks, H3K4me (H3 trimethylated at lysine 4) and H4K20me (H4 trimethylated at lysine 20) [6,7,8,9,10]. The latter interaction has been discovered later and, it has been less investigated. In a very recent study, it has been reported that Spindlin
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have