Synthetic Biology from the Perspective of Protein Design and Engineering
The primary basic research interests of our group is the informational aspect of the protein-folding problem; that is, how does the sequence of a protein determine its active, three-dimensional structure or fold? And then the application of understanding that we achieve in protein design & engineering and synthetic biology.
We tackle these areas using the following multi-disciplinary approach:
1. We use bioinformatics to garner sequence-to-structure relationships from protein sequence and structural databases.
2. We test the relationships (‘rules for protein folding’) that we find in two ways: (a) through ab initio protein-structure prediction; and (b) via rational protein design, where we engineer natural protein structures, or design new ones completely from scratch (so-called de novo design).
3. Then, we test our engineered and design proteins experimentally using biophysical methods. The peptides and proteins are made either by peptide synthesis, or via recombinant DNA methods and the expression of synthetic genes. The products and then characterised using methods including: solution-phase biophysics, structural biology and microscopy.
4. Finally, we explore potential applications of the designed and engineered proteins in the burgeoning fields of bionanotechnology and synthetic biology.
Synthetic biology presents challenges in fundamental and applied science, and in engineering. It asks if we understand enough about biology to modularise and standardise into parts; and, then, if such parts can be designed, engineered and combined in new ways to achieve new functions. True, we can engineer biological systems now, success is being achieved in the area, and we should continue this empirical, ambitious and sometimes even fanciful approach to the design and engineering of biology. However, I believe that big leaps will come through improved understanding of how biological systems are built and how they function.
This need for further understanding is certainly the case when it comes to designing and engineering proteins where we still haven’t cracked the protein-folding code, and we are a long way off designing or even tinkering with protein function, particularly enzyme activity, in predictable ways. That said, if we do not try we will never know how far these areas can be pushed. In addition, the synthetic-biology approach inspires us to dream up, and tackle ever more ambitious design and engineering goals. In my view, this new approach brings a breath of fresh air to the protein-design field.
I shall outline one view of what the field of synthetic biology is and might become in its broadest sense; and then how protein designers and engineers might benefit from and contribute to this exciting new area.
Bromley EHC, Channon K, Moutevelis E, Woolfson DN. 2008. Peptide and protein building blocks for synthetic biology: From programming biomolecules to self-organized biomolecular systems. ACS Chemical Biology 3: 38-50
Fletcher JM, Boyle AL, Bruning M, Bartlett GJ, Vincent TL, Zaccai NR, Armstrong CT, Bromley EHC, Booth PJ, RL Brady et al. 2012. A Basis Set of de novo Coiled-Coil Peptide Oligomers for Rational Protein Design and Synthetic Biology ACS Synthetic Biology (in press).
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