Theoretical Investigation of the role of water in hydrophobic key-lock association kinetics

小分子（配体）与疏水结合口袋的缔合在生物化学分子识别和功能中以及在水溶液的物理化学中的各种自组装过程中起着不可或缺的作用。结合过程通常由所谓的钥匙锁原理控制，其中形状互补的口袋和配体由于内在的和水介导的相互作用而缔合。虽然在过去的十年中，水对平衡结合自由能（亲和力）的贡献的研究吸引了大量的关注，但几乎没有人知道水在确定结合速率和动力学机制中的作用。例如，在疏水对接位点附近，配体扩散的纳米级流体动力学效应是什么？它们是如何被口袋的化学成分控制甚至操纵的？我们最近已经表明，通过分子模拟和扩散描述的一个简单的原型口袋配体模型，结合口袋内的水合波动可以大规模耦合到配体动力学和影响其结合率。由于水合波动又可以通过口袋的几何形状和极性进行修改，因此有可能产生良好控制的流体动力学波动，其加速或减速接近配体以获得所需的结合速率。在这个建议中，我们希望探索这样一个有吸引力的概念，理论上通过使用显式水分子模拟和扩展的扩散模型的通用钥匙锁系统在水溶剂中。将研究口袋的物理化学和几何性质以及溶剂的性质对局部扩散率和结合率的影响。各向异性配体将被用来研究旋光动力学耦合。非马尔可夫（记忆）效应应被识别和铸造成一个隐含的描述耦合随机扩散模型，以产生有效的粗粒度模型的利率预测。该项目的结果不仅将增加我们对（生物）分子结合过程的基本理解，而且将有助于设计功能性主客体系统以及优化生物医学应用中的药物。

The association of small molecules (ligands) with hydrophobic binding pockets plays an integral role in biochemical molecular recognition and function, as well as in various self-assembly processes in the physical chemistry of aqueous solutions. The binding process is typically governed by the so-called key-lock principle, in which the shape-complementary pocket and ligand associate due to intrinsic and water- mediated interactions. While the investigation of water contributions to the binding free energy (affinity) in equilibrium has attracted a great deal of attention in the last decade, almost nothing is known about the role of water in determining the rates of binding and kinetic mechanisms. For instance, what are the nanoscale hydrodynamic effects on ligand diffusion close to the hydrophobic docking site, and how are they controlled or even steered by the chemical composition of the pocket? We have recently shown by molecular simulations and diffusional descriptions of a simple prototypical pocket-ligand model that hydration fluctuations within the binding pocket can massively couple to the ligand dynamics and influence its binding rate. Since the hydration fluctuations in turn can be modified by the pocket geometry and polarity, the possibility opens up to create well-controlled hydrodynamic fluctuations which accelerate or decelerate approaching ligands to obtain a desired binding rate. In this proposal we want to explore such an appealing notion theoretically by using explicit-water molecular simulations and extended diffusion models on generic key-lock systems in aqueous solvent. The influence of the physicochemical and geometric properties of the pocket as well as the nature of the solvent on local diffusivities and binding rates will be studied. Anisotropic ligands will be investigated to study translational-rotational dynamical coupling. Non-Markovian (memory) effects shall be identified and cast into an implicit description by coupled stochastic diffusion models, in order to generate efficient coarse-grained models for rate prediction. The results of this project will add not only to our fundamental understanding of (bio)molecular binding processes but will be helpful for the design of functional host-guest systems as well as optimized drugs in biomedical applications.