Understanding Radical S-Adenosylmethionine Enzymes in silico

EPSRC Thematic Area - Computational Chemistry

Project background
A core principle of sustainable chemistry is the inclusion of catalysis in as many reaction steps as is possible, commonly achieved using extremely rare platinum group metals. Due to the finite and economically unsustainable nature of these elements there is a need for improvements in methods to reduce or reuse these metals, or for more sustainable options to be developed. One of these replacements is the use of biocatalysts, specifically enzymes, which also allow for a high level of control and therefore design, making this option an attractive one. Understanding how enzymes work and how they can be designed has benefits which go further than simply replacing platinum group catalysts; by opening up the possibility for new reaction pathways or improving the reaction conditions - indeed the majority of enzymes will only function at 'mild' conditions. Improvements to existing tools and the creation of new tools for chemistry, along with an increase in the understanding of biocatalytic processes is beneficial to a number of fields including medicine and manufacturing and therefore is relevant to a large section of society. The greatest challenge in producing these biocatalysts for practical purposes is gaining the knowledge and understanding sufficient to implement rational protein design.
An exhaustive search of every possible amino acid chain of every possible length would hypothetically result in a database of all possible enzyme functions, but even if the desired information could be derived from each chain in a single second a study on the chains of just length 14 would take longer than the current age of the universe. Clearly this problem cannot be solved through 'brute force', instead the basic principles behind protein folding and the relationship between amino acid sequence and function must be understood by investigating how specific mutations affect the structure and function of an enzyme, and therefore how we can design an enzyme for a particular function using only those basic principles. As the physical production and manipulation of enzymes for investigatory purposes can be very time consuming the speed and more importantly the control that computational methods provide make them a clear choice to tackle this problem.

Proposed solution and methodology
A combination of software and original code will be developed to create a system simulating the above and optimised by using known results from Radical SAM enzymes. While the main aim is to improve our understanding of enzyme catalysis in general, new or improved reactions relevant to other fields may be discovered as a result of this exploration. An investigation into the relationship between the amino acid sequence, structure and function of enzymes should begin with a rational choice of which family of enzymes to study.

This CDT will have a positive impact in the following areas:

PEOPLE. The primary focus is people and training. Industry needs new approaches to reach their sustainability targets and this is driving an increasing demand for highly qualified PhD graduates to lead innovation and manage change in the area of chemicals production. CDT based cohort training will provide industry ready scientists with the required technical competencies and drive to ensure that the sector retains its lead position in both innovation and productivity. In partnership with leading chemical producers and users, we will provide world class training to satisfy the changing needs of tomorrow's chemistry-using sector. Through integrated links to our Business School we will maximise impact by delivering dynamic PhD graduates who are business aware.

ECONOMY. Sustainability is the major issue facing the global chemical industry. Not only is there concern for our environment, there is also is a strong economic driver. Shareholders place emphasis on the Dow Jones Sustainability Index that tracks the performances of the sector and engenders competition. As a result, major companies have set ambitious targets to lower their carbon footprints, or even become carbon neutral. GSK CEO Sir Andrew Witty states that "we have a goal to reduce our emissions and energy use by 45% compared with 2006 levels on a per unit sales basis... " Our CDT will help companies meet these challenges by producing the new chemistries, processes and people that are the key to making the step changes needed.

SOCIETY. The diverse range of products manufactured by the chemical-using industries is vital to maintain a high quality of life in the UK. Our CDT will have a direct impact by ensuring a supply of people and new knowledge to secure sustainability for the benefit of all. The role of chemistry is often hidden from the public view and our CDT will provide a platform to show chemical sciences in a positive light, and to demonstrate the importance of engineering and applications across biosciences and food science.
The "green and sustainable" agenda is now firmly fixed in the public consciousness, our CDT will be an exemplar of how scientists and engineers are providing solutions to very challenging scientific and technical problems, in an environmentally benign manner, for the benefit of society. We will seek sustainable solutions to a wide range of problems, whilst working in sustainable and energy efficient facilities. This environment will engender a sustainability ethos unique to the UK. The CNL will not only serve as a base for the CDT but also as a hub for science communication.
Public engagement is a crucial component of CDT activities; we will invite input and discussion from the public via lectures, showcases and exhibition days. The CNL will form a hub for University open days and will serve as a soft interface to give school children and young adults the opportunity to view science from the inside. Through Dr Sam Tang, public awareness scientist, we have significant expertise in delivering outreach across the social spectrum, and she will lead our activities and ensure that the CDT cohorts engage to realise the impact of science on society. Martyn Poliakoff, in his role as Royal Society Foreign Secretary, will ensure that our CDT dovetails with UK science policy.

KNOWLEDGE. In addition to increasing the supply of highly trained people, the results of the PhD research performed in our CDT will have a major impact on knowledge. Our student cohorts will tackle "the big problems" in sustainable chemistry, and via our industrial partners we will ensure this knowledge is applied in industry, and publicised through high level academic outputs. Our knowledge-based activities will drive innovation and economic activity, realising impact through creation of new jobs and securing the future.