title: Protein design from in silico dynamic information: the emergence of the 'turn-dock-lock' motif.
abstract: A protein design methodology based on ab initio folding simulations is described and illustrated. First, the time evolution of the chain topology is generated to identify a collapse-triggering nucleus. Then, a minimal spliced sequence of nuclear residues is created and systematically mutated in silico until it can sustain a stable conformation retaining the original nucleus topology. The mutations introduce a structural compensation for the deletions and eventually lead to the recovery of the native fold motif beyond topological identity. For ubiquitin, the systematically modified sequence is predicted to be a resilient folder, since it is 92% homologous to the hyperthermophile variant of B1-domain in streptococcal protein G. The methodology enabling us to identify the nucleus is independently validated vis-á-vis site-directed mutagenesis experiments on chymotrypsin inhibitor (CI2).
authors.affiliation: Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Am Klopferspitz, 82152 Martinsried (bei München), Germany. arifer@criba.edu.ar
authors.forename: Ariel
authors.initials: A
authors.lastname: Fernández
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D003198:Computer Simulation; D017124:Conserved Sequence; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D010940:Plant Proteins; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods*; D017510:Protein Folding; D019154:Protein Splicing; D017386:Sequence Homology, Amino Acid; D014452:Ubiquitins / Q000737:chemistry / Q000235:genetics
chemical_list: D010455:Peptides; D010940:Plant Proteins; D014452:Ubiquitins; C093336:chymotrypsin inhibitor 2