Strategies to control the binding mode of de novo designed protein interactions

• Many computationally designed protein–protein interactions were reported over the past two years.
• Recent design goals include heterodimers, homodimers, homooligomers, fibril caps, and arrays.
• Diverse polar and nonpolar interaction motifs can control the binding orientation.
• Crystal structures show accurately designed interactions compared to atomic level predictions.
• Loops and hydrogen bond networks are outstanding interface design challenges.

There has been significant recent progress in the computational design of protein interactions including the creation of novel heterodimers, homodimers, nanohedra, fibril caps and a protein crystal. Essential to these successes has been the use of innovative strategies for finding binding modes that are achievable, that is, identifying binding partners and docked conformations that can be successfully stabilized via sequence optimization and backbone refinement. In many cases this has involved the use of structural motifs commonly found at naturally occurring interfaces including alpha helices inserted into hydrophobic grooves, beta-strand pairing, metal binding, established helix packing motifs, and the use of symmetry to form cooperative interactions. Future challenges include the creation of hydrogen bond networks and antibody-like interactions based on the redesign of protein surface loops.