How Much do Dispersion Interactions Contribute to Molecular Recognition in Solution?

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Chemistry

Abstract

The whole of chemistry and biology is driven by the interactions occurring between molecules. Such interactions determine the structure and activity of the molecular machinery of life; i.e. the DNA, proteins, enzymes and other biomolecules from which your body is assembled. Thus, quantifying the factors that influence the strength of intermolecular interactions can help us to understand the driving force behind many chemical and biological processes. Theoretical physics predicts that the strength of molecular interactions is determined by two main effects; electrostatic interactions (e.g. the attractive interaction between positive and negative charges), and dispersion interactions, the attractive component of so-called van der Waals interactions, which arise from transient fluctuations in the electron clouds of atoms that have been brought into close contact. In most cases electrostatic interactions are stronger than dispersion interactions, but this may not always be the case. For example, the incredible sticking power of geckos feet has been attributed to dispersion interactions!Intermolecular interactions must be measured on the molecular level to gain a complete, transferable understanding that can be used to predict the behaviour of other systems. Unfortunately, detailed study of interactions in biological systems is hindered due to the presence of complicated arrays of interactions featuring multiple molecular contacts and solvent molecules. Furthermore, in addition to the influence of solvent, interactions are also highly sensitive to the relative positioning of the interacting atoms, which is hard to define in large, flexible biomolecules. In contrast, structurally well-defined chemical systems allow the relationship between chemical structure and the energetics of intermolecular interactions to be systematically explored, facilitating the design of experiments that test specific aspects of theoretical and computational models. Previous experimental studies have shown that electrostatic effects dominate intermolecular interactions in solution, but this may not always be the case. For example, computational calculations predict that dispersion interactions might dominate over electrostatic effects when large extended molecular surfaces are brought into contact, but to date, no experimental studies have measured this effect or investigated the role of the solvent in a systematic way.This proposal seeks to address this fundamental hole in our knowledge of intermolecular interactions using simple synthetic chemical complexes to quantify the interactions between extended molecular surfaces in a range of different solvents. The favourable design of these complexes will facilitate conclusive comparisons to be made between theory and experiment. This work offers the potential of revealing new or overlooked physical phenomena. Such discoveries will be of practical utility to the whole scientific and industrial community. This study will help to solve one of the major barriers in the development of reliable methods for predicting molecular behaviour. For example, this research could guide the development of new advanced materials, and novel highly-potent pharmaceutical agents. The resulting advances will ultimately benefit the economy, health and the quality of life of the UK general public and beyond.

Planned Impact

WHO WILL BENEFIT AND HOW WILL THEY BENEFIT? This programme combines experimental physical organic chemistry, synthetic organic chemistry and computational chemistry to tackle a fundamental problem that underpins the whole of chemistry and biology. In addition to providing a wealth of quantitative experimental data against which theoretical models of solvation and non-covalent interactions can be tested, this work may reveal new or overlooked physical phenomena. Such discoveries will be of practical utility to the whole academic and industrial chemistry community. It will help to solve one of the major barriers in the development of reliable methods for predicting molecular behaviour. For example, this research could lead to the development of reliable methods for predicting compound solubility, new materials, advances in the fields of molecular self-assembly (a central aspect of 'bottom-up nanotechnology'), and an improved understanding of protein-ligand interactions could guide the development of novel highly-potent pharmaceutical agents. The resulting advances will ultimately benefit the economy, health and the quality of life of the UK general public and beyond. In addition to the theoretical advances and the potential applications, the PDRA working on the project will also benefit from research training in the disciplines of physical organic chemistry, computational chemistry and synthetic organic chemistry. The EPSRC has identified physical organic chemistry as a strategic research area which needs to be strengthened and encouraged within the UK to address the industrial need for people with the appropriate skills in this area. They are also aiming to encourage early career academics (such as myself and the PDRA who will work on this project) into the discipline of physical organic chemistry. COMMUNICATION & ENGAGEMENT The applicant is establishing a track record of publishing articles in the leading chemistry Journals, with two of the most recent articles being further highlighted in Nature, and Nature Nanotechnology. The applicant seeks to publish in general science and chemistry journals rather than specialist niche publications for two main reasons. Firstly, this maximises exposure to the work, and secondly it ensures ensure that the research is written in an accessible form, allowing the impact of the findings to be understood and realised by those beyond the original field of research. The ability to communicate and disseminate information is an important generic skill. Thus, the PDRA working on this project will be expected to play an active role in publication writing and delivery of research presentations. Additional opportunities for transferable skills development in communication, public outreach and entrepreneurship will be offered by the Scottish Institute for Enterprise and the University of Edinburgh Transkills Unit (which is recognised by the UK Research Councils as a Centre of Excellence in the provision of generic and transferable skills training). COLLABORATORS Despite being a new group, we have already established a number of interdisciplinary and international collaborations. These collaborators are likely to be the first to benefit from relevant discoveries emerging from the proposed research, but it is expected that the proposed dissemination plans will enable other beneficiaries to identify and exploit such findings. The PDRA working on this project will have the opportunity to interact and work with any of our current collaborators where appropriate. EXPLOITATION Well-established infrastructure exists in Edinburgh to support exploitation through commercialisation. Edinburgh Research and Innovation (ERI) seek to promote the University's research and commercialisation activities to potential research sponsors and collaborators, licensees or investors. ERI will assist in seeking out partners, accessing suitable funds, and managing intellectual property issues and its exploitation.

Publications

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Yang L (2014) Can non-polar hydrogen atoms accept hydrogen bonds? in Chemical communications (Cambridge, England)

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Yang L (2015) Quantifying Solvophobic Effects in Nonpolar Cohesive Interactions. in Journal of the American Chemical Society

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Yang L (2016) Can Dispersion Forces Govern Aromatic Stacking in an Organic Solvent? in Angewandte Chemie (International ed. in English)

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Mati IK (2010) Molecular balances for quantifying non-covalent interactions. in Chemical Society reviews

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Adam C (2015) Partitioning solvophobic and dispersion forces in alkyl and perfluoroalkyl cohesion. in Angewandte Chemie (International ed. in English)

 
Description Van der Waals dispersion forces are one of the least understood classes of molecular interactions. We have discovered through several different investigations that van der Waals dispersion forces are at least an order of magnitude weaker in solution compared to the gas phase. Several high impact publications detail these results in Nature Chemistry, J. Am. Chem. Soc. and Angew. Chem. Int. Ed.
Exploitation Route Our fundamental results have implications for the computational prediction of molecular recognition phenomenon occurring in solution. We have highlighted major inadequacies in current computational methods.
Sectors Agriculture, Food and Drink,Chemicals,Digital/Communication/Information Technologies (including Software),Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Afton Chemical Corporation
Amount £80,000 (GBP)
Funding ID 3.5 year CASE studentship 
Organisation Afton Chemical 
Sector Private
Country United States
Start  
 
Description iCASE Award with Syngenta
Amount £49,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 08/2014 
End 08/2018
 
Description iCASE Award with Syngenta
Amount £49,000 (GBP)
Organisation Syngenta International AG 
Sector Private
Country Switzerland
Start 08/2014 
End 08/2018
 
Description Getting van der Waals forces right 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience
Results and Impact Highlight on work on dispersion interactions conducted by Cockroft group featured on the "In the Pipeline Blog", the worlds-first science blog.
Year(s) Of Engagement Activity 2013
 
Description Van der Waals Force Measured In Solution 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience
Results and Impact Highlight of work on dispersion interactions by Cockroft group published on C&E News (ISSN 0009-2347)
Year(s) Of Engagement Activity 2013
 
Description Will the sky fall as Dr says no to strong 'bond' 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience
Results and Impact RSC Chemistry World highlight of work on dispersion interactions by Cockroft and co-workers published in Nature Chemistry.
Year(s) Of Engagement Activity 2013