ArticleProtein science : a publication of the Protein Society2013
A comparison of successful and failed protein interface designs highlights the challenges of designing buried hydrogen bonds.
Article in Protein science : a publication of the Protein Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 153 papers.
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153 citing papers in PubMed.
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- Structure-guided analysis and prediction of human E2-E3 ligase pairing specificity.bioRxiv : the preprint server for biology · 2026Article
- Improved protein binder design using β-pairing targeted RFdiffusion.Nature communications · 2026Article
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Abstract
The accurate design of new protein-protein interactions is a longstanding goal of computational protein design. However, most computationally designed interfaces fail to form experimentally. This investigation compares five previously described successful de novo interface designs with 158 failures. Both sets of proteins were designed with the molecular modeling program Rosetta. Designs were considered a success if a high-resolution crystal structure of the complex closely matched the design model and the equilibrium dissociation constant for binding was less than 10 μM. The successes and failures represent a wide variety of interface types and design goals including heterodimers, homodimers, peptide-protein interactions, one-sided designs (i.e., where only one of the proteins was mutated) and two-sided designs. The most striking feature of the successful designs is that they have fewer polar atoms at their interfaces than many of the failed designs. Designs that attempted to create extensive sets of interface-spanning hydrogen bonds resulted in no detectable binding. In contrast, polar atoms make up more than 40% of the interface area of many natural dimers, and native interfaces often contain extensive hydrogen bonding networks. These results suggest that Rosetta may not be accurately balancing hydrogen bonding and electrostatic energies against desolvation penalties and that design processes may not include sufficient sampling to identify side chains in preordered conformations that can fully satisfy the hydrogen bonding potential of the interface.
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