DichroCalc: DNA Dichroism Calculations

In 1953, Crick and Watson deciphered the structure of DNA from the X-ray data of Franklin, Gosling and Wilkins, thereby laying the foundation of modern day molecular biology and molecular medicine. It is almost impossible to overstate the impact - scientific, medical and economic - that understanding the structure of DNA has had in the 20th and 21st centuries. In this proposal, we seek to provide a computational tool for relating the structure of DNA in SOLUTION to biophysical experiments that measure the interaction of DNA with polarized light. Such experiments can complement other approaches, using NMR or infrared spectroscopy. Probing the conformation of DNA as its binds other molecules provides valuable information on its interactions with other molecules and could be the first step in understanding a huge range of processes at the heart of molecular biology. Despite the clear importance of a fully quantitative theory relating structure to optical spectroscopy, such a theory has yet to be realized. Expertise developed at Nottingham over the past decade makes us almost uniquely well-placed to advance the theory necessary to calculate the optical spectroscopy of DNA accurately. This will involve quantum chemical calculations on Nottingham's 12-teraflop high performance computer (HPC). In addition, our web-server, DichroCalc, is the only one world-wide, where scientists can upload biological macromolecular structures and get back a calculated circular dichroism spectrum. Thus, we will be able to disseminate the results of research quite readily and make them accessible to the scientific research community in an-easy-to-use fashion.

The spectroscopies of linear and circular dichroism (LD and CD) provide powerful tools for detecting structural changes in nucleic acid structure, which might occur, for example, upon binding a ligand. Probing the interactions of DNA with small molecules and proteins is an area which is fundamental to biomedical research at a molecular level. This research programme will seek to provide a deeper understanding of the relationship between the structure(s) of DNA and the corresponding optical spectra. Our research over the past decade has led to considerable improvements in the accuracy in first principles' calculations of the CD spectra of proteins. The advances in protein electronic structure calculations have been based on state of the art ab initio quantum chemical calculations of the amide chromophore, side chain aromatic chromophores and charge transfer transitions in di-amides. This expertise should be readily translatable to nucleic acids. In the first part of the project, we propose to perform ab initio calculations of the individual chromophoric bases and charge transfer transitions between monomers; in the second part, these will be used to compute the LD and CD of a variety of interesting protein-DNA and DNA conformations. Calculations on large polymeric DNAs require approximations, such as the exciton approach. These are not yet fully quantitative and even for single base pairs there are some ambiguities in quantum chemical ab initio calculations on monomeric bases. In this respect, the precise orientation of the electric transition dipole moments is critical. This programme of research promises to open exciting new areas of application encompassing both polymeric DNA and protein-ligand complexes. We will make this computational tool available through our web-server DichroCalc. This proposal will extend the functionality of DichroCalc significantly, enabling calculations on DNA and providing a useful new tool to the biophysical research community.

Research into the fundamental aspects of the structure of DNA in solution and the interactions in DNA-protein and DNA-ligand complexes has an impact over a wide range of biological sciences. By understanding the fundamentals we are in a strong position to explore the design of molecules to regulate biological function. Thus, the beneficiaries will be (i) the academic research community of biochemists and cell biologists searching for a molecular basis for normal and malfunctioning cellular behaviour; (ii) medicinal chemistry and molecular modellers trying to predict the behaviour and function of important biomolecules, and (iii) the pharmaceutical companies engaged in programmes of drug discovery. Such a fundamental understanding of molecular interactions in biology underpins much of the wealth creation from the biotech and pharmaceutical industry. The importance and benefits of the research are, therefore, that it underpins a wide range of biotechnology and our fundamental concepts in drug discovery and targeting. The latter clearly has wider benefits to the general public by underpinning basic pharmaceutical research which will lead to new medicines to tackle 21st century 'grand challenges' in global healthcare. The highly skilled PDRAs and PhD students that we produce will most certainly lead ultimately to wealth creation through the applications of this transferable skills base. The maximum impact of the research will be achieved through open access to the results, which will be achieved principally through rapid and open publication which will be accessible to the largest possible number of beneficiaries. In the event that there is something of potential commercial value, the School of Chemistry is well set up with a Business Partnership Unit and Manager for exploiting the impact of the research. The Unit was the first of its kind in the UK. It promotes and establishes contacts between the School and business. It is managed by a full time Business Development Manager, Dr T. Farren. The School has established collaborations with a wide range of companies, including major international corporations and local SMEs.