Protein Structure Design and Engineering

Abstract Protein structure design and engineering is a research endeavour in which proteins with predicted structure and function are constructed in the laboratory through rational design, combinatorial selection or combination of both approaches. It is built upon our knowledge about the structure and function of proteins and can be accomplished either from scratch (de novodesign) or based on native scaffolds (redesign). The area of protein design is an exciting and rapidly growing field, advancing from the design of simple protein structures, to those that are more complicated and recently to the designs of functional proteins. Design of artificial proteins containing unnatural amino acids, backbone linkages or cofactors have also been reported, making it possible to prepare proteins with structural and functional properties beyond those of native proteins. These advances bring us closer to realising the dream of tailor‐made artificial enzymes with high catalytic efficiency and selectivity for biotechnological and pharmaceutical applications. Key Concepts: Protein structure design and engineering is a research endeavour in which proteins with predicted structure and function are constructed in the laboratory. The protein design field can be organised into two complimentary approaches: rational design and combinatorial selection of the desired protein. Rational protein design strategies can involve designing a protein from scratch (de novodesign) or redesigning a protein with native scaffolds to achieve new structures and functions. Combinatorial approaches can involve sampling a large population of proteins to select the desired one or it can involve numerous rounds of randomised mutation followed by selection to fine‐tune properties being selected for. Techniques are available that allow the incorporation of unnatural moieties, such as unnatural amino acids, backbone linkages or cofactors, into proteins. The field has made a big stride recently in designing functional proteins.