Lanzarotti Esteban, Defelipe Lucas A, Marti Marcelo A, Turjanski Adrián G
Departamento de Computación, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
J Cheminform. 2020 May 8;12(1):30. doi: 10.1186/s13321-020-00437-4.
Aromatic rings are important residues for biological interactions and appear to a large extent as part of protein-drug and protein-protein interactions. They are relevant for both protein stability and molecular recognition processes due to their natural occurrence in aromatic aminoacids (Trp, Phe, Tyr and His) as well as in designed drugs since they are believed to contribute to optimizing both affinity and specificity of drug-like molecules. Despite the mentioned relevance, the impact of aromatic clusters on protein-protein and protein-drug complexes is still poorly characterized, especially in those that go beyond a dimer. In this work, we studied protein-drug and protein-protein complexes and systematically analyzed the presence and structure of their aromatic clusters. Our results show that aromatic clusters are highly prevalent in both protein-protein and protein-drug complexes, and suggest that protein-protein aromatic clusters have idealized interactions, probably because they were optimized by evolution, as compared to protein-drug clusters that were manually designed. Interestingly, the configuration, solvent accessibility and secondary structure of aromatic residues in protein-drug complexes shed light on the relation between these properties and compound affinity, allowing researchers to better design new molecules.
芳香环是生物相互作用中的重要残基，在很大程度上作为蛋白质-药物和蛋白质-蛋白质相互作用的一部分出现。由于它们天然存在于芳香族氨基酸（色氨酸、苯丙氨酸、酪氨酸和组氨酸）以及设计药物中，它们与蛋白质稳定性和分子识别过程都相关，因为据信它们有助于优化类药物分子的亲和力和特异性。尽管有上述相关性，但芳香簇对蛋白质-蛋白质和蛋白质-药物复合物的影响仍未得到很好的表征，特别是在那些超出二聚体的复合物中。在这项工作中，我们研究了蛋白质-药物和蛋白质-蛋白质复合物，并系统地分析了它们芳香簇的存在和结构。我们的结果表明，芳香簇在蛋白质-蛋白质和蛋白质-药物复合物中都非常普遍，并表明与人工设计的蛋白质-药物簇相比，蛋白质-蛋白质芳香簇具有理想化的相互作用，这可能是因为它们通过进化得到了优化。有趣的是，蛋白质-药物复合物中芳香残基的构型、溶剂可及性和二级结构揭示了这些性质与化合物亲和力之间的关系，使研究人员能够更好地设计新分子。
