Function and emergent behaviour in the radical SAM enzyme superfamily – computational studies of the role of protein evolution and dynamics on biocatalysis
Supervisors: Dr Anna K Croft, Faculty of Engineering, Biomechanism Engineering Laboratory
Professor Jonathan D Hirst, School of Chemistry
The relationship between enzyme function and structure, with a view to protein re-engineering, is still a highly complex field of study, with emergent reactions still being only able to be broadly predicted from either sequence or structure. With the increased interest in industrial biotransformations, to replace fossil fuels as sources of bulk and fine chemicals, the need for discovery of new biocatalysts and their rational re-engineering is more pressing than ever.
Radical reactions, which are able to transform inactivated C-H bonds and perform other highly chemically-challenging functionalisations, have been underexploited in biotechnology. In particular, radical reactions initiated by S-Adenosyl methionine (SAM, Figure 1) have evolved in nature to catalyse a wide range of useful transformations, including those that can uniquely modify biochemical building blocks as routes to new bioactive materials. Understanding the principles of the reactions of this class of enzymes, can aid not only in engineering new reactions, but can contribute to the development of new catalysts and a better understanding of the control of free radicals. With over 110,000 sequences (although few known crystal structures) of these enzymes now available, we propose to use a systems approach to delineate both common principles and chemical evolution from a structural perspective, utilising a combination of intensive structural bioinformatics coupled with atomistic molecular dynamics simulations.
Figure 1. (a) An example radical SAM enzyme highlighting key co-factor elements (iron-sulfur clusterin yellow, S-Adenosyl methionine CPK) and underpinning barrel structure. (b) The S-Adenosyl methionine cofactor cleavage reaction to generate the key intermediate radical common to all radical SAM enzymes.
This project will use high-performance computer simulations, including molecular dynamics, homology modelling, statistical and networks-based approaches, with the principal objective of analysing how nature is able to control and manipulate free radical chemistry, and how the structural elements of these enzymes relate to the substrates. The information gained will be utilised to assess the key components of radical chemistry that both control the type of chemistry enacted by the enzyme, and the mechanisms that the enzyme utilises for handling highly reactive species. From this, designs for either new enzymes (rational protein engineering) or catalysts embodying the key elements of these enzymes will be developed and fed into concurrent experimental work and collaborations.
Student profile: You should be excited by interdisciplinary working and have a track record in either Chemistry, Biochemistry, Chemical/Biochemical Engineering, Computing, Mathematics or a closely-related discipline. Previous experience with statistical analysis, quantum chemistry, molecular dynamics, programming and/or various quantum mechanics or molecular dynamics software tools would be beneficial.
Summary: UK students - Tuition Fees paid, and full Stipend of £13,863 (2014/15 rate), EU students Tuition Fees paid. A tailored training programme to enable our researchers to develop key skills in the development and understanding of complex systems and a seminar series from leading academics in areas related to complex systems and processes.
Eligibility: applicants will need to be eligible for Engineering and Physical Sciences Research Council (EPSRC) funding so need to be from the UK or EU. Full eligibility criteria can be found on the EPSRC site: http://www.epsrc.ac.uk/skills/students/help/eligibility/