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

Abstract

A new tool in the protein design toolbox Protein design can compute protein folds from first principles. However, designing new proteins that are functional remains challenging, in part because designing binding interactions requires simultaneous optimization of protein sequence and protein-ligand conformation. Polizzi and DeGrado designed proteins from scratch that bind a small-molecule drug (see the Perspective by Peacock). They introduced a new structural element called a van der Mer (vdM), which tracks the orientation of a chemical group relative to the backbone of a contacting residue. Assuming proteins bind ligands using interactions similar to intraprotein packing, they determined statistically preferred vdMs from a large set of structures in the Protein Data Bank. By including weighted vdMs in their computations, they designed two of six de novo proteins that bind the drug apixaban. A drug-protein x-ray crystal structure confirmed the designed model. Science , this issue p. 1227 ; see also p. 1166