Recent advances in automated protein design and its future challenges.

INTRODUCTION: Protein function is determined by protein structure which is in turn determined by the corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are understood, it should be possible to refine or even redefine the function of a protein by working backwards from the desired structure to the sequence. Automated protein design attempts to calculate the effects of mutations computationally with the goal of more radical or complex transformations than are accessible by experimental techniques. Areas covered: The authors give a brief overview of the recent methodological advances in computer-aided protein design, showing how methodological choices affect final design and how automated protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion: Automated protein design holds potential as a protein engineering technique, particularly in cases where screening by combinatorial mutagenesis is problematic. Considering solubility and immunogenicity issues, automated protein design is initially more likely to make an impact as a research tool for exploring basic biology in drug discovery than in the design of protein biologics.