Pharmacoinformatics Unit, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
National Laboratory for Drug Research and Development, Magyar tudósok krt. 2, H-1117 Budapest, Hungary.
Int J Mol Sci. 2024 May 29;25(11):5945. doi: 10.3390/ijms25115945.
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 address 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 this 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 in root mean squared deviations from the experimental references. The influence of structural factors and explicit hydration on the performance of post-docking MD refinements are also discussed to help with their implementation in future methods and applications.
组蛋白是许多表观遗传事件的关键，其复合物具有治疗和诊断意义。确定组蛋白复合物的结构对于设计新药至关重要。计算分子对接广泛用于预测靶标-配体复合物。由于其构象灵活性大、水合作用广泛且与阅读器蛋白的浅结合口袋相互作用较弱，像组蛋白尾部这样的大线性肽是对接的挑战性配体。因此，快速对接方法通常无法产生此类肽配体的复杂结构，无法满足药物设计的要求。为了解决这一挑战，并提高对接复合物的结构质量，已经应用了各种分子动力学 (MD) 方法进行对接后精修。然而，对于所需的 MD 精修方案，尚未达成最终共识。在本研究中，针对一组具有较大对接几何结构误差的组蛋白肽配体的问题复合物，系统地探索了 MD 精修策略。比较了在 MD 模拟参数方面存在差异的六个方案。在所有情况下，都应用了复合物界面区域的预 MD 水合作用，以避免出现不需要的空腔。表现最佳的方案在对接结构的基础上，在均方根偏差变化方面取得了中位数 32%的改善，以更接近实验参考值。还讨论了结构因素和显式水合作用对对接后 MD 精修性能的影响，以帮助在未来的方法和应用中实施这些因素。
