title: Computational protein design: the Proteus software and selected applications.
abstract: We describe an automated procedure for protein design, implemented in a flexible software package, called Proteus. System setup and calculation of an energy matrix are done with the XPLOR modeling program and its sophisticated command language, supporting several force fields and solvent models. A second program provides algorithms to search sequence space. It allows a decomposition of the system into groups, which can be combined in different ways in the energy function, for both positive and negative design. The whole procedure can be controlled by editing 2-4 scripts. Two applications consider the tyrosyl-tRNA synthetase enzyme and its successful redesign to bind both O-methyl-tyrosine and D-tyrosine. For the latter, we present Monte Carlo simulations where the D-tyrosine concentration is gradually increased, displacing L-tyrosine from the binding pocket and yielding the binding free energy difference, in good agreement with experiment. Complete redesign of the Crk SH3 domain is presented. The top 10000 sequences are all assigned to the correct fold by the SUPERFAMILY library of Hidden Markov Models. Finally, we report the acid/base behavior of the SNase protein. Sidechain protonation is treated as a form of mutation; it is then straightforward to perform constant-pH Monte Carlo simulations, which yield good agreement with experiment. Overall, the software can be used for a wide range of application, producing not only native-like sequences but also thermodynamic properties with errors that appear comparable to other current software packages.
authors.affiliation: Laboratoire de Biochimie (CNRS UMR7654), Department of Biology, Ecole Polytechnique, Palaiseau, 91128, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Simonson
authors.forename: Thomas
authors.initials: T
authors.lastname: Gaillard
authors.forename: David
authors.initials: D
authors.lastname: Mignon
authors.forename: Marcel
authors.initials: M
authors.lastname: Schmidt am Busch
authors.forename: Anne
authors.initials: A
authors.lastname: Lopes
authors.forename: Najette
authors.initials: N
authors.lastname: Amara
authors.forename: Savvas
authors.initials: S
authors.lastname: Polydorides
authors.forename: Audrey
authors.initials: A
authors.lastname: Sedano
authors.forename: Karen
authors.initials: K
authors.lastname: Druart
authors.forename: Georgios
authors.initials: G
authors.lastname: Archontis
mesh_terms: D000465:Algorithms; D019295:Computational Biology; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D058767:Protein Unfolding; D011506:Proteins / Q000737:chemistry*; D050737:Proto-Oncogene Proteins c-crk / Q000737:chemistry; D012984:Software; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D011506:Proteins; D050737:Proto-Oncogene Proteins c-crk; D014443:Tyrosine; D014448:Tyrosine-tRNA Ligase
keywords: Monte Carlo; aminoacyl-tRNA synthetase; computer simulation; molecular recognition; protein engineering