Computation-Based Design and Engineering of Protein and Antibody Therapeutics

Recent advances in computation-based protein engineering offer opportunities to introduce or modify the biophysical characteristics of proteins at will. The power of computational design comes from the ability to surpass the combinatorial and physical limitations inherent to laboratory-based high-throughput or trial-and-error methods. As a result, modifications that require significant changes to the amino acid sequence of a protein are now accessible to the protein engineering community. Hydrophobic cores of proteins have been repacked to increase their thermostability. Binding sites in proteins have been modified to increase affinity or alter specificity for proteins, peptides, and small molecules. Enzymes have been designed de novo. Non-natural protein folds have been created. For the most part, these achievements have been applied to proteins that make good model systems in academic settings. How can these computational methods be applied to therapeutically relevant proteins? This review will focus on the ground-breaking achievements of computation-based protein engineering and on recent applications of rational design to improve therapeutic proteins.