The past, present and future of de novo protein design

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Notes

shift in protein engineering from random selection to intentional computational design methods (1)

long-standing challenges of designing new protein structures, assemblies and protein binders are close to being solved (1)

what to design, and open-source design methodology such as RFdiffusion and ProteinMPNN together with protein structure prediction tools (1)

de novo design of small-molecule target binders, enzymes and multistate protein systems (1)

design of catalysts for reactions with high energy barriers (1)

design of switches and nanomachines that integrate binding, conformational change and catalysis (1)

sophisticated functionality of natural proteins evolved over hundreds of millions of years of natural selection to solve the problems that were critical during biological evolution (1)

functionality and versatility of the proteins in nature suggests that new proteins could provide solutions to many of these problems (1)

de novo protein design: building new proteins with new functions from the ground up rather than by repurposing existing native proteins (1)

first, for the general reader, to provide an overview of the progress in this area (2)

second, for scientists outside of the field, to encourage the application of protein design methods to their research problems (2)

third, for methods developers, to encourage focus on unsolved rather than largely solved design problems (2)

Protein design challenges

major classes of challenges that de novo protein design (2)

design of monomeric protein folds and multiprotein assemblies (2)

proteins that bind to other proteins (2)

small-molecule binders, sensors and enzyme catalysts (2)

multistate functional biomolecular systems (2)

Protein design methodology

Typical workflow.