Computational design of proteins targeting the conserved stem region of influenza hemagglutinin

By Sarel Jacob Fleishman, Timothy A. Whitehead, D. Ekiert, C. Dreyfus, J. Corn, Eva-Maria Strauch, Ian A. Wilson, David Baker. 2011

600 citations recorded by the source corpus.

Proteins can be designed that bind to specific patches on target proteins to alter their subsequent interactions. We describe a general computational method for designing proteins that bind a surface patch of interest on a target macromolecule. Favorable interactions between disembodied amino acid residues and the target surface are identified and used to anchor de novo designed interfaces. The method was used to design proteins that bind a conserved surface patch on the stem of the influenza hemagglutinin (HA) from the 1918 H1N1 pandemic virus. After affinity maturation, two of the designed proteins, HB36 and HB80, bind H1 and H5 HAs with low nanomolar affinity. Further, HB80 inhibits the HA fusogenic conformational changes induced at low pH. The crystal structure of HB36 in complex with 1918/H1 HA revealed that the actual binding interface is nearly identical to that in the computational design model. Such designed binding proteins may be useful for both diagnostics and therapeutics.

Subfields: Epidemiology, Molecular Biology, Radiology, Nuclear Medicine and Imaging

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Citations in the corpus

High resolution comparative modeling with RosettaCM (2013, background): “…realistic all atom energy function to achieve atomic accuracy in many challenging structural biology problems, including structure determination with sparse experimental data and the design of new protein structures and interfaces(Fleishman et al., 2011; King et al., 2012; Raman et al., 2010).”
Achievements and Challenges in Computational Protein Design. (2017, methodology): “In 2011 the Baker lab took the challenge of PPI and designed a protein that binds to the conserved stem surface of influenza hemagglutinin [86].”
Emerging themes in the computational design of novel enzymes and protein–protein interfaces (2013, background): “…acid residues that were predicted to form a dense network of stabilizing interactions among themselves, as in the design of protein inhibitors [54], amino acids with short sidechains, as in the design of oligomeric structures [57], or focused on designing interactions that utilize backbone…”
Computational design of a protein-based enzyme inhibitor. (2013, positive): “[11]) to the active-site region of HEL, followed by several rounds of refined docking and sequence design of scaffold residues proximate to the interface using the ROSETTA design methodology [18 – 20].”
How Good is Automated Protein Docking? (2013, methodology): “3, which was designed by the Baker group to replace an antibody binding to the stem region of influenza hemagglutinin,36 and Target T51, involving a xylanase enzyme containing six modules.”
A Generic Program for Multistate Protein Design (2011, background): “design, finding a low energy sequence compatible with a given backbone has been used to produce several proteins that adopt that backbone conformation; in protein interface design, finding a low-energy sequence compatible with a particular docked orientation of the two proteins has been used to prod”
The future of molecular dynamics simulations in drug discovery (2011, methodology): “The Rosetta molecular modeling approach, for instance, has proven to be very powerful (see, e.g., [95, 96]).”
Designing Peptides on a Quantum Computer (2019, background): “…protein topologies ( 2 , 3 ) , large macromolecular assemblies ( 4 – 7 ) , proteins with the ability to bind to toxic small molecules ( 8 , 9 ) or to other proteins of therapeutic interest ( 10 , 11 ) , and enzymes able to catalyze reactions that no known natural enzyme can catalyze ( 12 , 13 ) .”