title: Computational design of a symmetric homodimer using β-strand assembly.
abstract: Computational design of novel protein-protein interfaces is a test of our understanding of protein interactions and has the potential to allow modification of cellular physiology. Methods for designing high-affinity interactions that adopt a predetermined binding mode have proved elusive, suggesting the need for new strategies that simplify the design process. A solvent-exposed backbone on a β-strand is thought of as "sticky" and β-strand pairing stabilizes many naturally occurring protein complexes. Here, we computationally redesign a monomeric protein to form a symmetric homodimer by pairing exposed β-strands to form an intermolecular β-sheet. A crystal structure of the designed complex closely matches the computational model (rmsd = 1.0 Å). This work demonstrates that β-strand pairing can be used to computationally design new interactions with high accuracy.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: P Benjamin
authors.initials: PB
authors.lastname: Stranges
authors.forename: Mischa
authors.initials: M
authors.lastname: Machius
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Miley
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathy
authors.forename: Brian
authors.initials: B
authors.lastname: Kuhlman
mesh_terms: D018360:Crystallography, X-Ray / Q000379:methods; D004247:DNA / Q000737:chemistry; D019281:Dimerization; D004926:Escherichia coli / Q000378:metabolism; D008027:Light; D008968:Molecular Conformation; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012542:Scattering, Radiation; D012984:Software; D012997:Solvents; D013499:Surface Properties; D013816:Thermodynamics; D014461:Ultracentrifugation
chemical_list: D011506:Proteins; D012997:Solvents; D004247:DNA