title: Nativelike structure in designed four alpha-helix bundles driven by buried polar interactions.
abstract: We show that a single internal polar interaction per helix is sufficient to engender structural specificity in that helix in helical bundle proteins. Furthermore, we use histidine-binding cofactors of different shapes which bind directly into the core, demonstrating that this structural specificity is not the result of a prescribed complimentary, "knobs in holes" core packing. We show that we can switch structural specificity of individual helices on and off by ligating cofactors, singly and in pairs, which bind either one or two histidine ligands. To our knowledge, this is the first demonstration of such extensive manipulation of protein structure by ligand binding, an important result of general interest to those working with self-assembled molecular systems. Finally, as these proteins were designed without the use of computational modeling, we not only demonstrate that designing a uniquely structured cofactor binding protein is not as difficult as is generally believed, we have determined why this is so: hydrophobic core complementarity, which is very difficult to design, is not necessary. Instead, a much simpler design process entails the creation of core polar interactions which themselves can drive conformational specificity.
authors.affiliation: The Johnson Research Foundation and the Department of Biochemistry and Biophysics, The University of Pennsylvania, Philadelphia, Pennsylvania 19104-6059, USA.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Koder
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Valentine
authors.forename: Jose
authors.initials: J
authors.lastname: Cerda
authors.forename: Dror
authors.initials: D
authors.lastname: Noy
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Smith
authors.forename: A Joshua
authors.initials: AJ
authors.lastname: Wand
authors.forename: P Leslie
authors.initials: PL
authors.lastname: Dutton
mesh_terms: D006860:Hydrogen Bonding; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D010455:Peptides