The Non-Covalent Chemistry of Complex Systems

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.

Although this project is fundamental in nature, it has the potential for widespread impact across a broad spectrum of technologies. The aim is to establish a general model for the prediction of the properties of non-covalent interactions for an unprecedented range of complex systems. The physical properties as well as most of the functional properties of molecular systems in chemistry, biology and materials science all strongly affected or governed by non-covalent interactions. Although computational methods can now begin to make useful predictions about structure, especially for biopolymers that have evolved to adopt a single well-defined conformation, our ability to make predictions about thermodynamic properties lags far behind. The proposed development of a quantitative relationship between chemical structure and the thermodynamics of non-covalent interactions will unlock the doorway to a new era in rational molecular design in many areas where trial and error or random screening currently represent the state of the art, e.g. drug design, catalysis, sensors and smart materials. There are many apparently simple but important problems that one can imagine tackling from first principles based on chemical structure, e.g. mixing and solubility, but more empirical approaches are the current state of the art. If molecular engineering is to become a reality in the 21st century, the development of any genuine form of synthetic non-biological nanotechnology will require an intimate appreciation of the specifications of the basic building materials, i.e. we must learn the relationship between chemical structure, non-covalent interactions and properties. The insights arising from this research program will therefore be directly applicable in fields like organocatalysis, biocatalysis, transition metal catalysis, process chemistry, drug design, sensor design, molecular machines, smart polymers and nanotechnology to name a few areas where there is much current activity. An understanding of the thermodynamics of molecular interactions at complex interfaces is important in many areas. For example, in engine lubrication, thermodynamics governs the assembly of additives at interfaces between moving parts but quantitative prediction of behaviour is difficult. Tribology provides many other illustrations of engineering problems that depend upon the thermodynamics of molecules at interfaces. In adhesion, control of the interfacial free energy is critical to achieving strong, durable bonding. Empirical data typically rely upon contact angle measurement, peel tests and related methods; the availability of quantitative models for prediction of interfacial free energies under different conditions could greatly facilitate the development of enhanced adhesive systems and a better understanding of the factors determining adhesive performance.

The project will produce four scientists with training and expertise that spans the traditional disciplines of organic, inorganic, physical and theoretical chemistry, with experience of working in a collaborative team. This breadth of experience will be united by a quantitative approach to understanding molecular phenomena. The interdisciplinary nature of the work will equip the appointees for work at the interfaces with other disciplines, which is where they are likely to have to most impact in their future research careers. A knowledge of non-covalent chemistry underpins almost all of the chemical industries: pharmaceutical, agrochemicals, dyes, liquid crystals and polymers, including basic R&D, chemical engineering, manufacturing and process chemistry. The applicants collaborate with a range of pharmaceutical, agrochemical and computational drug discovery companies, so there is plenty of potential for knowledge transfer and industrial input to the project through these interactions.