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.

Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis

“…A similar conclusion was reached for a pair of Glu and Asp residues in the pocket P6 of DR and I-E molecules 44 . We used the empirical model Propka 45 and a constant-pH Monte Carlo approach implemented in the program PROTEUS 46 to compute the pK of titratable groups in the crystallographic structure of HLA-DQ8, both in the absence and the presence of the peptides insulin and VCL-DERAA. Both methods agreed that the residues aGLU31 and bGLU86, near pocket P1, are strongly correlated; the predicted pKa values suggested that one of them should be protonated, most probably aGlu31.…”

Dead-End Elimination with a Polarizable Force Field Repacks PCNA Structures

“…Future applications of many-body DEE may help determine whether the use of polarizable force fields (26) and self-consistent reactionfield implicit solvents (28)(29)(30) can overcome the limitations of previous generation pairwise force fields (14) and pairwise implicit solvents (21-23) for computational protein design (15)(16)(17).…”

“…The combination of low-energy side-chain rotamer libraries (8)(9)(10) with DEE (11,12) global optimization has been widely used for protein electrostatic network optimization and sequence design (13)(14)(15)(16)(17). However, rotamer elimination criteria have only been defined for pairwise-additive energy functions such as the OPLS-AA (18), AMBER (19), and CHARMM (20) families of fixed partial-charge force fields and pairwise decomposable continuum solvents (21)(22)(23).…”

Recombinant human dihydroxyacetonephosphate acyl-transferase characterization as an integral monotopic membrane protein

“…The secondary structure prediction resulted from the comparison of the following servers: HHpred, Quick2D [23], PredictProtein [24], Proteus 2.0 [25]. The transmembrane (TM) helices/region prediction was performed by interrogating the following servers: POLYVIEW-2D (117–138) [26], TMAP (115–132, 168–196, 370–398, 565–580) [27], TMPRED (8–25, 165–194) [28], Octopus (510–560) [29].…”