Do the amino acid sequence identities of residues that make contact across protein interfaces covary during evolution? If so, such covariance could be used to predict contacts across interfaces and assemble models of biological complexes. We find that residue pairs identified using a pseudo-likelihood-based method to covary across protein–protein interfaces in the 50S ribosomal unit…

Since apopotosis of infected cells can limit virus production and spread, some viruses have co-opted prosurvival genes from the host. This includes the Epstein-Barr virus gene BHRF1, a homologue of human Bcl-2 proteins that block apoptosis and are associated with cancer. Here we describe an approach where computational design and experimental optimization were used to…

The self-assembly of proteins into highly ordered nanoscale architectures is a hallmark of biological systems. The sophisticated functions of these molecular machines have inspired the development of methods to engineer self-assembling protein nanostructures; however, the design of multi-component protein nanomaterials with high accuracy remains an outstanding challenge. Here we report a computational method for designing protein nanomaterials in which multiple copies of two distinct subunits co-assemble…

King, C. et al. PNAS 111, 8577-82 (2014) Immune reposes can make protein therapeutics ineffective or even dangerous. Here we describe a general computational protein design method for reducing immunogenicity by eliminating known and predicted T-cell epitopes and maximizing the content of human peptide sequences without disrupting protein structure and function. We show that the method…

Rajagopalan, S., Wang, C., et al. Nat Chem Bio. 10(5), 386-391 (2014) A challenge in the computational design of enzymes is that multiple properties, including substrate binding, transition state stabilization and product release, must be simultaneously optimized, and this has limited the absolute activity of successful designs. Here, we focus on a single critical property…

Correia, B.E. et al. Nature 507, 201-6 (2014) Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed.…

Tinberg, C.E., Khare, S.D., et al. Nature. 501(7466), 212-216. (2013) We describe a computational approach for designing proteins that bind small molecules and use it to create binders for digoxin, a steroid toxin deriving from the foxglove plant. The method relies on the explicit design of highly energetically favorable interactions with the ligand. Directed laboratory evolution…