Despite the wealth of knowledge gained from over a century of protein and enzyme research, we have yet to build successfully an artificial enzyme comparable to those found in nature. This remains a great challenge in biochemistry that once overcome, has the potential in providing cost-effective routes to new drugs, tailored therapies, efficient industrial processes, alternative energy sources and supplies of green fuels. We contend that the origin of this modest success lies within the layers of complexity that are imprinted onto natural proteins through the course of evolution.
However, we believe that such complexity can be controlled by using simple artificial proteins - neoproteins - untouched by natural selection. This approach is illustrated through our successful assembly of a heme-containing artificial neoprotein designed to reversibly bind oxygen. We aim to build on this recent successful de novo design to create the first artificial oxidoreductase enzymes capable of binding and activating oxygen towards chemical transformations. We plan to achieve this through the design and assembly of functional neoprotein components that integrate engineering elements present in natural oxidoreductases - electron transfer, oxygen binding - into robust artificial protein scaffolds. With function established in neoproteins encapsulation and formation of simple metabolic pathways in coacervate droplets will proceed, providing an excellent synthetic environment that resembles cellular conditions in a robust protocell. This project will therefore yield insights into natural enzyme assembly en route to the delineation of guidelines for constructing inexpensive protein catalysts and inform the assembly of biologically inspired encapsulated synthetic systems.
http://www.bris.ac.uk/biochemistry/research/ra.html
References:
Moser, C.C., Anderson, J.L.R., Dutton, P.L., (2010) Guidelines for tunneling in enzymes. BBA-Bioenergetics, 1797, 1573-1586.
Davydov, R.M., Chauhan, N., Thackray, S.J., Anderson, J.L.R., Papadopoulou, N.D., Mowat, C.G., Chapman, S.K., Raven, E.L., Hoffman, B.M., (2010) Probing the ternary complexes of indoleamine and tryptophan 2,3-dioxygenases by cryoreduction EPR and ENDOR spectroscopy. J. Am. Chem. Soc. 132, 5494-5500.
Koder, R.L.*, Anderson, J.L.R.*, Solomon, L.A., Reddy, K.S., Moser, C.C., Dutton, P.L. (2009) Design and engineering of an O2 transport protein. Nature 458, 305-310.
Anderson, J.L.R., Koder, R.L., Moser, C.C., Dutton, P.L. (2008) Controlling complexity and water penetration in functional de novo design. Biochem. Soc. Trans. 36, 1106-1111.