Bayarsaikhan, B.; Zsidó, B.Z.; Börzsei, R.; Hetényi, C. Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols. Preprints2024, 2024041782. https://doi.org/10.20944/preprints202404.1782.v1
APA Style
Bayarsaikhan, B., Zsidó, B.Z., Börzsei, R., & Hetényi, C. (2024). Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols. Preprints. https://doi.org/10.20944/preprints202404.1782.v1
Chicago/Turabian Style
Bayarsaikhan, B., Rita Börzsei and Csaba Hetényi. 2024 "Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols" Preprints. https://doi.org/10.20944/preprints202404.1782.v1
Abstract
Histones are keys to many epigenetic events and their complexes have therapeutic and diagnostic importance. The determination of the structures of histone complexes is fundamental in the design of new drugs. Computational molecular docking is widely used for the prediction of target-ligand complexes. Large, linear peptides like the tail regions of histones are challenging ligands for docking due to their large conformational flexibility, extensive hydration, and weak interactions with the shallow binding pockets of their reader proteins. Thus, fast docking methods often fail to produce complex structures of such peptide ligands at a level appropriate for drug design. To answer this challenge, and improve the structural quality of the docked complexes, post-docking refinement has been applied using various molecular dynamics (MD) approaches. However, a final consensus has not been reached on the desired MD refinement protocol. In the present study, MD refinement strategies were systematically explored on a set of problematic complexes of histone peptide ligands with relatively large errors in their docked geometries. Six protocols were compared that differ in their MD simulation parameters. In all cases, pre-MD hydration of the complex interface regions was applied to avoid the unwanted presence of empty cavities. The best-performing protocol achieved a median of 32 % improvement over the docked structures in terms of the change of root mean squared deviations from the experimental references. The influence of structural factors and explicit hydration on the performance of post-docking MD refinements was also discussed to help their implementation in future methods and applications.
Keywords
peptide; histones; docking; refinement; molecular dynamics; water
Subject
Computer Science and Mathematics, Mathematical and Computational Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
