The Non-Covalent Chemistry of Complex Systems

对非共价相互作用的准确定量描述将为解开凝聚相分子性质的复杂性提供关键。尽管我们开始有信心地预测三维结构，但目前对决定功能性质的热力学的预测仍然遥不可及。在21世纪，我们渴望分子工程学科，但这种描述与任何试图生产功能分子的实验室实际发生的事情还有很长的路要走。这项提议的目的是开发一系列新的工具，使人们能够基于对分子间作用力的新的超分子观点，准确地将分子性质映射到化学结构上。我们选择分子表面上特定识别位置之间的单个点接触作为我们的参照系。这些是我们可以在实验系统中很容易识别和量化的相互作用类型。这将使我们能够在根据第一性原理计算的分子参数与超分子模型系统的实验行为和分子系综的整体性质之间建立联系。我们认为，这种方法有可能对非共价化学如何决定复杂体系的功能性质并跨越分子科学的所有学科提供全新的见解。这些方法将在代表当前实际和科学挑战的一系列分子设计问题中进行测试，例如预测蛋白质-配体亲和力、相分配、溶解度、共晶形成、表面粘连、摩擦和反应性的非共价控制。其目标是产生一种通用的方法来预测和理解任何分子体系的热力学性质。这种新的超分子表面接触方法有望彻底改变我们对溶液、界面和固体中分子相互作用的看法，这种方式可以被参与分子科学的每个人采用。

An accurate quantitative description of non-covalent interactions will provide the key to unravelling the complexity of condensed phase molecular properties. Although we are beginning to be able to predict three-dimensional structure with some confidence, prediction of the thermodynamics that dictate functional properties remains well beyond our reach at present. In the 21st century, we aspire to the discipline of molecular engineering, but this description is a long way from the reality of what actually takes place in any laboratory that attempts to produce a functional molecule. The aim of this proposal is to develop a range of new tools that will allow the accurate mapping of molecular properties onto chemical structure, based on a new supramolecular perspective on intermolecular forces. We choose as our frame of reference individual point contacts between specific recognition sites on molecular surfaces. These are the types of interactions that we can easily identify and quantify in experimental systems. This will allow us to build a connection between molecular parameters that can be calculated from first principles with the experimental behaviour of supramolecular model systems and the bulk properties of molecular ensembles. We believe that this approach has the potential to deliver radically new insights into how non-covalent chemistry determines the functional properties of complex systems and cuts across all disciplines in the molecular sciences. The methods will be tested in a range of molecular design problems that represent current practical and scientific challenges, such as prediction of protein-ligand affinity, phase partitioning, solubility, cocrystal formation, surface adhesion, friction and non-covalent control of reactivity. The goal is to produce a general method for predicting and understanding the thermodynamic properties of any molecular system. This new supramolecular surface contact approach promises to completely change the way we think about the molecular interactions in solutions, interfaces and solids in a way that can be adopted by everyone involved in the molecular sciences.