Computational Protein Design - Wodak Lab

Computational protein design has become an increasingly valuable tool for helping biochemists design protein variants with desired properties in a rational manner and for investigating sequence-structure relations in ways that were not previously possible. We contributed to these developments with our work on the protein design software DESIGNER. This software takes as input the 3D structure of a given protein and computes a set of amino acid sequence that are likely to adopt that structure. The selected sequences are those that minimise a fitness function, which measures the stability of the resulting protein. Unlike most other protein design procedures the fitness function computed by DESIGNER relies on general physical chemical principles that govern protein stability. In addition, the calculations are performed on sets of backbone conformations belonging to closely related proteins. Using the DESIGNER we have been investigating the influence of stability and structural constraints on shaping the sequence space of proteins and studying ways of improving the protein design methodology in a physically meaningful manner.

In parallel we showed that our protein design approach is also capable of producing useful practical results, with potential medical applications. Using DESIGNER we computed amino acid sequences of peptides likely to bind the HLA-A2 MHC class-I allele. The 10 lowest energy peptide sequences were chemically synthesized and shown to bind the expected MHC protein. Among those, 3 peptides displayed significant inhibition of CD8+ T cell recognition, suggesting that they might interfere with autoimmune reactions. More recently in collaboration with Donald Hilvert, Martin Karplus and Alfonso Jaramillo, DESIGNER has been applied to redesign helices in chorismate mutase, using a minimized amino acid alphabet. We are currently testing the application of DESIGNER to the problems of protein recognition and 3D domain swapping.

To learn more:

  • 10966779
    Wernisch L., Hry S. & Wodak S.
    Automatic protein design with all atom force-fields by exact and heuristic optimization
    J. Mol. Biol., 301(3): 713-36
  • 12411444
    Ogata K, Alfonso Jaramillo, William Cohen, Jean-Paul Briand, Francine Connan, Jeannine Choppin, Sylviane Muller, and Shoshana J. Wodak
    Automatic sequence design of MHC Class-I binding peptides impairing CD8+ T cell recognition.
    J. Biol. Chem., 278 (2), 1281-1290
  • 15377512
    Jaramillo A. and Wodak S.J.
    Protein Design is a challenge for Implicit Solvation Models.
    Biophysical J. Jan ;88(1) :156-71
Wodak Lab:
Computational Protein Design