Recent advances in computational protein design

Proteins are the molecules cells primarily rely on for catalysis, recognition, signaling, defense, locomotion, and structural integrity. Engineering proteins for improved function or new applications is a fast-growing segment of biotechnology and biomedicine. Experimental efforts based on the screening of large mutant libraries have led to many successes but they do not provide quantitative design principles and/or insight into the structural features that underpin the desired function. The computational de novo design of proteins promises to bridge this gap; however, it requires reliable structure prediction, provisions for protein stability, and accurate descriptions of inter-molecule interactions. Studies that successfully meet all these criteria are beginning to emerge including the design of an O2-binding protein and a novel enzyme that catalyzes a Diels–Alder reaction.

► Modeling of protein function hinges upon accurate structure prediction. ► Proteins must be stable at the desired operating conditions. ► Inter-molecule interactions dictate the specifics of protein function. ► Successful de novo protein design requires meeting multiple criteria.