Lešnik Samo, Jukić Marko, Bren Urban
Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, 2000, Maribor, Slovenia.
IOS, Institute of Environmental Protection and Sensors, Beloruska 7, 2000, Maribor, Slovenia.
J Cheminform. 2025 Apr 10;17(1):50. doi: 10.1186/s13321-025-00997-3.
Our study investigates polyphenol-protein interactions, analyzing their structural diversity and dynamic behavior. Analysis of the entire Protein Data Bank reveals diverse polyphenolic structures, engaging in various noncovalent interactions with proteins. Interactions observed across crystal structures among diverse polyphenolic classes reveal similarities, underscoring consistent patterns across a spectrum of structural motifs. On the other hand, molecular dynamics (MD) simulations of polyphenol-protein complexes unveil dynamic binding patterns, highlighting the influx of water molecules into the binding site and underscoring limitations of static crystal structures. Water-mediated interactions emerge as crucial in polyphenol-protein binding, leading to variable binding patterns observed in MD simulations. Comparison of high- and low-resolution crystal structures as starting points for MD simulations demonstrates their robustness, exhibiting consistent dynamics regardless of the quality of the initial structural data. Additionally, the impact of glycosylation on polyphenol binding is explored, revealing its role in modulating interactions with proteins. In contrast to synthetic drugs, polyphenol binding seems to exhibit heightened flexibility, driven by dynamic water-mediated interactions, which may also facilitate their promiscuous binding. Comprehensive dynamic studies are, therefore essential to understand polyphenol-protein recognition mechanisms. Overall, our study provides novel insights into polyphenol-protein interactions, informing future research for harnessing polyphenolic therapeutic potential through rational drug design.Scientific contribution: In this study, we present an analysis of (natural) polyphenol-protein binding conformations, leveraging the entirety of the Protein Data Bank structural data on polyphenols, while extending the binding conformation sampling through molecular dynamics simulations. For the first time, we introduce experimentally supported large-scale systematization of polyphenol binding patterns. Moreover, our insight into the significance of explicit water molecules and hydrogen-bond bridging rationalizes the polyphenol promiscuity paradigm, advocating for a deeper understanding of polyphenol recognition mechanisms crucial for informed natural compound-based drug design.
我们的研究调查了多酚 - 蛋白质相互作用，分析了它们的结构多样性和动态行为。对整个蛋白质数据库的分析揭示了多样的多酚结构，这些结构与蛋白质进行各种非共价相互作用。在不同多酚类别的晶体结构中观察到的相互作用揭示了相似性，强调了一系列结构基序中的一致模式。另一方面，多酚 - 蛋白质复合物的分子动力学（MD）模拟揭示了动态结合模式，突出了水分子流入结合位点，并强调了静态晶体结构的局限性。水介导的相互作用在多酚 - 蛋白质结合中起着关键作用，导致在MD模拟中观察到可变的结合模式。以高分辨率和低分辨率晶体结构作为MD模拟的起点进行比较，证明了它们的稳健性，无论初始结构数据的质量如何，都表现出一致的动力学。此外，还探讨了糖基化对多酚结合的影响，揭示了其在调节与蛋白质相互作用中的作用。与合成药物相比，多酚结合似乎表现出更高的灵活性，这是由动态水介导的相互作用驱动的，这也可能促进它们的混杂结合。因此，全面的动态研究对于理解多酚 - 蛋白质识别机制至关重要。总体而言，我们的研究为多酚 - 蛋白质相互作用提供了新的见解，为未来通过合理药物设计利用多酚治疗潜力提供参考。科学贡献：在本研究中，我们利用关于多酚的蛋白质数据库结构数据的整体，对（天然）多酚 - 蛋白质结合构象进行了分析，同时通过分子动力学模拟扩展了结合构象采样。我们首次引入了实验支持的多酚结合模式的大规模系统化。此外，我们对明确水分子和氢键桥接重要性的洞察使多酚混杂范式合理化，主张更深入地理解对基于天然化合物的明智药物设计至关重要的多酚识别机制。
