Unveiling polyphenol-protein interactions: a comprehensive computational analysis.

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.