Christof Martin Jäger

Christof Jaeger photo

Project Title: 

Radical Enzymes in Biotechnology - Pioneering with Computational Chemistry

Host Organisation: 

Faculty of Engineering – Manufacturing and Process Technologies Research Division, University of Nottingham

Short Biography

Following my undergraduate studies of Molecular Science I received my PhD in Computational Chemistry from the University of Erlangen-Nuernberg, Germany in 2010.  I then worked as a Postdoc  for the Cluster of Excellence Engineering Advanced Materials (EAM) until 2014, when I joined the Biorenewables and Bioprocessing Research Group in in the Faculty of Engineering of the University of Nottingham.

My research experience includes Molecular Dynamics simulations, semi-empirical Molecular Orbital Theory, DFT and ab initio methods and force field development. Past projects involved multi-disciplinary research in the areas of bio-organic, colloid, and radical chemistry, molecular self-assembly, ion effects, and molecular electronics in organic electronic devices.

My CASCADE-FELLOWS fellowship directly progressed into the advanced Nottingham Research Fellowship (NRF) which I was able to secure on a highly competitive level. This fellowship will be followed by a permanent position at the Faculty of Engineering at the University of Nottingham, subject to performance. I plan to settle and expand my collaborations and develop a research group at the intersection of computational chemistry and applied biotechnology. My vision is to develop predictive modelling methodologies that pioneer experimental advances in the context of sustainable chemistry in both academic and industrial communities. I want to build a virtual lab delivering world leading research at the intersection of high-impact, detailed biochemical understanding and applied biotechnology, which significantly influences the development of novel biotechnological approaches.

Brief description of research project

This project’s primary aim was to promote radical S-adenosylmethionine (rSAM) enzymes for biotechnological applications by methods of computational chemistry. This supports the eminent need for new and improved biocatalysts for sustainable industrial biotechnological applications that can substitute crude oil based chemical synthesis.
Radical enzymes offer the opportunity to combine sustainable chemistry approaches with the high potential of free radicals. Their high reactivity often leads to an inadvertent broad spread of products, but nature has been able to harness them to generate a wide range of selectively-produced valuable materials including antibiotics, anticancer, and antiviral drugs.

Starting from a detailed case study of 7-Carboxy-7-deazaguanine (CDG) synthase (QueE) first the radical reaction mechanism in this radical SAM enzyme was investigated, delivering detailed understanding of the radical rearrangement steps in QueE. It was revealed that a distinct conformational change initiated by counterion complexation forces the substrate radical into a conformation allowing the central ring contraction and preventing other otherwise favourable side reactions. This effect comes along with a significant destabilisation of the substrate radical intermediate. This is an unprecedented behaviour of radical enzymes presenting transition state stabilisation instead of radical stabilisation for radical control of this reaction, and shows how important the radical control in these enzymes is.

In combination with molecular dynamic simulations a simulation strategy has been developed that involves the calculation of the stability of radical intermediates in form of so called radical stabilisation energies (RSEs). In that way it is possible to evaluate the thermodynamic radical reaction profile and how it is influenced by the enzyme. This is part of further development and a recently submitted grant application. It gives important insights into radical control, essential for engineering these enzymes towards alternative substrates and functionality. The outcomes support substantial understanding and insights into biochemical reaction mechanisms and is thus highly relevant for the biocatalysis research community and the ongoing development of efficient simulation strategies benefit the computational chemistry community and also everybody aiming for efficient computational strategies for enzyme design approaches.

Along this case study the foundation for developing an innovative, partly automated, and computationally affordable computer-based simulation and analysis strategy for an efficient investigation of other rSAM enzymes was laid. The strategy involves MD simulations and efficient analysis (e.g. based on principal component analysis), QM evaluation of thermodynamic reaction properties and control by higher level kinetic computations. It has been applied successfully to other examples like lysine aminomutase (LAM) and is matter of further ongoing developments. The development also led to detailed investigation of the conformational space of SAM in collaboration with NMR experts. This has revealed previously unknown details of the conformational behaviour of SAM using combined experimental and simulation methods. Initiated collaborative work with experimental experts will now drive the developments and applications towards enzyme design of rSAM enzymes, bringing them in the focus of biotechnological applications.