VOLUME 523. Methods in Protein Design

Available here.

"In the past 20 years, significant progress has been made in methods for designing proteins. Advances in experimental protein library screening, for example, using phage or yeast-surface display now enable discovery efforts in many companies and have led to the development of protein therapeutics used in the clinic. Computational protein design, which was until quite recently a purely academic pursuit, is being widely used outside of the laboratories of the original developers. Chemical strategies for diversifying protein backbones, for example, making them less susceptible to proteolysis, are maturing. Applications for these methods abound and include design of novel protein interaction reagents based on non-antibody scaffolds, design of peptide-based inhibitors, design of highly stabilized proteins, design of new enzymatic functions, and prediction of the effects of mutations on stability, binding affinity and specificity, and drug resistance." "Despite progress, protein design remains very challenging. The fundamental problem of how to search vast sequence and conformational spaces efficiently, using either experimental screens/selections or computational sampling, still demands innovative solutions. And our ability to predict the relative stabilities of different proteins from their sequences is quite primitive. The chapters presented here represent the state of the art in several ways. First, they demonstrate what is possible using existing methods. In cases where methods have matured to the point that they are routinely applied in their developers’ labs, formal protocols are presented so that others can use these techniques. This is the case for several powerful experimental screening and selection methods. Second, where capabilities are not as mature, important tools are presented. Several chapters describe software packages, algorithms, or scripts that are available to help users try their own versions of protein design. Third, assessment methods are presented for judging and potentially improving the quality of existing energy functions and for assessing the quality of candidate designs. Interspersed throughout, there are ideas and suggestions about how to confront challenging problems including target selection, conformational sampling, multistate design, and library design."