Nick Polizzi’s latest work describing the development of a new tool for protein design is published in Science

This week, DGL postdoc Nick Polizzi published a paper in Science describing the development of a new tool for protein design: the van der Mer (vdM). vdMs use structural information for a large set of proteins in the PDB to map the location of a chemical group to the backbone position of a contacting amino acid. A small-molecule ligand can be decomposed into a number of chemical groups important for binding, and vdMs can then be used to describe the collective interactions of the protein with the molecule. Protein-chemical group interactions can be ranked based on the PDB-prevalence of the vdMs that describe them, which helps with choosing which interactions to use in a design. By choosing prevalent vdMs and then performing flexible backbone sequence design, proteins can be designed from scratch that tightly and specifically bind a target small molecule. Nick demonstrated the approach by designing two (of six) proteins that bind the small-molecule drug apixaban. A high-resolution crystal structure of one of the designs showed the protein-drug interactions predicted by vdMs were largely achieved. Until now, efforts to design small-molecule binding proteins have critically relied on experimentally sifting through large, randomized sequence libraries to achieve binding. vdMs may provide a streamlined approach to solving a variety of protein-design and chemical-biology problems from first principles.

For more info, see the thoughtful Perspective written by Anna Peacock (U. Birmingham) in Science (Can proteins be truly designed sans function?) and the news article in Chemistry World (Viewpoint shift designs drug binding proteins from scratch).

Congratulations to Nick on this great paper!

A defined structural unit enables de novo design of small-molecule–binding proteins.