title: Computational design of proteins targeting the conserved stem region of influenza hemagglutinin.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sarel J
authors.initials: SJ
authors.lastname: Fleishman
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Whitehead
authors.forename: Damian C
authors.initials: DC
authors.lastname: Ekiert
authors.forename: Cyrille
authors.initials: C
authors.lastname: Dreyfus
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Corn
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Strauch
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: David
authors.initials: D
authors.lastname: Baker
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019151:Peptide Library; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012984:Software
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D019151:Peptide Library; D011506:Proteins; C483468:hemagglutinin, human influenza A virus