Ptaszek Aleksandra L, Kratzwald Sarah, Sagan Filip, Migotti Mario, Sánchez-Murcia Pedro A, Konrat Robert, Platzer Gerald
Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology, Department of Structural and Computational Biology, Max Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
Laboratory of Computer-Aided Molecular Design, Division of Medicinal Chemistry, Otto-Loewi Research Center, Medical University of Graz, Neue Stiftintalstr. 6/III, A-8010 Graz, Austria.
J Phys Chem B. 2025 May 22;129(20):4917-4928. doi: 10.1021/acs.jpcb.5c00155. Epub 2025 May 12.
Understanding weak interactions in protein-ligand complexes is essential for advancing drug design. Here, we combine experimental and quantum mechanical approaches to study the streptavidin-biotin complex, one of the strongest interacting protein-ligand systems. Using a monomeric streptavidin mutant, we analyze H NMR chemical shift perturbations (CSPs) of biotin upon binding, identifying remarkable upfield shifts of up to -3.2 ppm. Quantum chemical calculations attribute these shifts primarily to aromatic ring currents, with additional contributions from charge transfer effects linked to weak interactions. The agreement between experimental and computed chemical shifts validated the X-ray structure as a reliable basis for detailed computational analyses. Energy decomposition analysis reveals that electrostatics dominate the biotin-streptavidin interaction, complemented by significant orbital and dispersion contributions. Notably, weak noncovalent interactions, such as CH···S, CH···π, and CH···HC contacts, driven by London dispersion forces, contribute ∼44% to the complex's stability.
了解蛋白质 - 配体复合物中的弱相互作用对于推进药物设计至关重要。在此，我们结合实验和量子力学方法来研究链霉亲和素 - 生物素复合物，这是相互作用最强的蛋白质 - 配体系统之一。使用单体链霉亲和素突变体，我们分析了生物素结合时的¹H NMR化学位移扰动（CSPs），发现高达 -3.2 ppm的显著高场位移。量子化学计算将这些位移主要归因于芳香环电流，以及与弱相互作用相关的电荷转移效应的额外贡献。实验和计算化学位移之间的一致性验证了X射线结构作为详细计算分析的可靠基础。能量分解分析表明，静电作用主导了生物素 - 链霉亲和素相互作用，并伴有显著的轨道和色散贡献。值得注意的是，由伦敦色散力驱动的弱非共价相互作用，如CH···S、CH···π和CH···HC接触，对复合物的稳定性贡献约44%。
