Fink Michael J, Syrén Per-Olof
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
School of Chemical Science and Engineering, Division of Applied Physical Chemistry, KTH Royal Institute of Technology, 100 44 Stockholm, Sweden; Science for Life Laboratory, KTH Royal Institute of Technology, 171 21 Stockholm, Sweden.
Curr Opin Chem Biol. 2017 Apr;37:107-114. doi: 10.1016/j.cbpa.2017.02.013.
Herein we highlight recent findings on the importance of water networks in proteins, and their redesign and reconfiguration as a new engineering strategy to generate enzymes with modulated binding affinity and improved catalytic versatility. Traditionally, enzyme engineering and drug design have focused on tailoring direct and favorable interactions between protein surfaces and ligands/transition states to achieve stronger binding, or an accelerated manufacturing of medicines, biofuels, fine chemicals and materials. In contrast, the opportunity to relocate water molecules in solvated binding pockets by protein design to improve overall energetics remains essentially unexplored, and fundamental understanding of the elusive processes involved is poor. Rewiring water networks in protein interiors impacts binding affinity, catalysis and the thermodynamic signature of biochemical processes through dynamic mechanisms, and thus has great potential to enhance binding specificity, accelerate catalysis and provide new reaction mechanisms and chemistry, that were not yet explored in nature.
在此，我们重点介绍了关于蛋白质中水网络的重要性的最新研究发现，以及将其重新设计和重新配置作为一种新的工程策略，以生成具有调节结合亲和力和更高催化多功能性的酶。传统上，酶工程和药物设计专注于调整蛋白质表面与配体/过渡态之间直接且有利的相互作用，以实现更强的结合，或加速药物、生物燃料、精细化学品和材料的制造。相比之下，通过蛋白质设计重新定位溶剂化结合口袋中的水分子以改善整体能量学的机会基本上尚未得到探索，并且对所涉及的难以捉摸的过程的基本理解也很匮乏。在蛋白质内部重新布线水网络通过动态机制影响结合亲和力、催化作用和生化过程的热力学特征，因此具有增强结合特异性、加速催化作用并提供自然界尚未探索的新反应机制和化学性质的巨大潜力。
