COSTBI-587; NO OF PAGES 8 Please cite this article in press as: Channon K, et al., Synthetic biology through biomolecular design and engineering, Curr Opin Struct Biol (2008), doi:10.1016/j.sbi.2008.06.006 Available online at www.sciencedirect.com Synthetic biology through biomolecular design and engineering Kevin Channon 1 , Elizabeth HC Bromley 1 and Derek N Woolfson 1,2 Synthetic biology is a rapidly growing field that has emerged in a global, multidisciplinary effort among biologists, chemists, engineers, physicists, and mathematicians. Broadly, the field has two complementary goals: To improve understanding of biological systems through mimicry and to produce bio- orthogonal systems with new functions. Here we review the area specifically with reference to the concept of synthetic biology space, that is, a hierarchy of components for, and approaches to generating new synthetic and functional systems to test, advance, and apply our understanding of biological systems. In keeping with this issue of Current Opinion in Structural Biology, we focus largely on the design and engineering of biomolecule-based components and systems. Addresses 1 School of Chemistry, University of Bristol, Bristol BS8 1TS, UK 2 Department of Biochemistry, University of Bristol, Bristol BS8 1TD, UK Corresponding author: Woolfson, Derek N (D.N.Woolfson@bristol.ac.uk) Current Opinion in Structural Biology 2008, 18:1–8 This review comes from a themed issue on Engineering and design Edited by Dek Woolfson and Lynne Regan 0959-440X/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.sbi.2008.06.006 Introduction Complexity in Nature is astounding, and attempts to mimic it present considerable challenges and potential rewards. This complexity stems from a hierarchical organ- ization of biomolecular components and layers of inter- actions between them. Encouragingly, many aspects of both the components and their interactions are becoming increasingly understood. As outlined below, this hierarch- ical view and our improved understanding of and ability to engineer biology are the cornerstones of synthetic biology. We refer to the potentially vast arena in which synthetic biologists can operate as synthetic biology space. This is represented as a plot of complexity of components against some indicator of how divergent from Nature these are (i.e. how ‘synthetic’ the components are) (Figure 1). We find this useful in two respects: First it provides a frame- work to chart routes toward the common goal of creating multi-component, encapsulated, functional systems; second, it allows a wide variety of studies to be grouped into a small number of general approaches. We believe that this will be useful in defining and, hopefully, helping to develop the exciting and broad area of synthetic biology. For this review, because of the breadth of topics that contribute to this emerging field, we found it necessary to refer to classic studies from the past two decades, reviews in various areas from the past five years, as well as more recent work from the past three years. Synthetic biology space: hierarchies of components, interactions and approaches At the base of the hierarchy is a set of basic units—amino acids, nucleic acids, sugars and lipids 1 (Figure 1). One level of complexity above these are what might be termed tectons. This term is borrowed from supramolecular chem- istry [1], where it is used to describe programmed mol- ecular components and nanoscale building blocks [2]. An example of a nucleic acid tecton would be a short oligo- nucleotide containing the information for further assem- bly through interactions with other tectons. Similarly, an amino acid based tecton would be a polypeptide designed to form stretches of self-assembling a-helix or b-strands. Importantly, a tecton is something more than a simple element of secondary structure: It implies that the element contains information about its further assembly into prescribed higher order structures. Combining tec- tons leads to the next level in the hierarchy, in which self- assembled units are formed through interactions pro- grammed into tectons. For peptides and proteins, autonomous folding motifs would be self-assembling units. By prudent organization of such units one can arrive at functional assemblies. As with tectons, the defi- nitions of self-assembling unit and functional assembly encompass functional protein and DNA tertiary and quaternary structures. With further organization, interact- ing networks of functional assemblies – that is, systems – can be constructed. In Nature, complex interacting com- ponents of a system are almost always contained, or encapsulated, within lipid membranes, which enable cells to maintain control over their environments, and the biochemical processes they conduct. Here, we use the concept of synthetic biology space (Figure 1) to capture the assembly of these various components and 1 There are, of course, many other small molecules involved in biological processes. However, a large fraction of the structural complex- ity of organisms can be represented in this small subset of building blocks. www.sciencedirect.com Current Opinion in Structural Biology 2008, 18:1–8