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Combinatorial Protein Design

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Creative Biolabs provides professional Combinatorial Protein Design services and technical supports for your protein engineering research.

Combinatorial approaches are a prominent method used for protein design to make enough variants of proteins for the analysis of their structures and stabilities. Applications could be seen in the identification of the amino acids responsible for important protein functions, the variability of folding sequences in a common structure and also the de novo protein design, all of which can be employed to produce therapeutics, sensors, catalysts and other materials.

Computational methods have been used to facilitate the process of combinatorial protein design. They can realize a much wider range of sequence variability permitted by desired functional and structural constraints, and provide quantitation methods for sorting and isolating the sequence space.

Strategies Offered using Computational Methods:

  1. Related sequences alignment analysis
  2. Protein profile construction with directed search methods
  3. Statistical analysis of sequence ensembles
  4. Gene library construction for specific protein profiles

Figure 1. General scheme used to design combinatorial mutation libraries based on computational protein design calculations. (Proc Natl Acad Sci USA. 2010)

Combinatorial peptide libraries displayed on bacteriophage have been used to identify specific receptors that have been found to be over-expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells. Peptides with specific affinities for such cell-surface receptors potentially enables accurate target of tumor cells by, therapeutic agents in vivo.

Computational methods are often employed to help the combinatorial library design. In searching for new potent pyrrolidine carboxamide inhibitors of enoyl-acyl carrier proteinreductase of Mycobacterium tuberculosis (MTb), 3D models of the protein-inhibitor complexes were built; a training set of 20 such inhibitors with known inhibitory effects were then used to compute a gas phase quantitative structure-activity relationships (QSAR) model. These finally led to the proposal of novel potent antituberculotic agent candidates with favorable pharmacokinetic properties.

In combinatorial protein design, there is a strong need to restrict the exponentially large number of possible sequences of a library. Theoretical tools to bias and characterize the items in a library are greatly needed. For example, exogenous enzymes, signaling peptides, and other classes of non-human proteins can be a potential pool of biotherapeutic agents. However, they may need to be deimmunized without affecting the stability or therapeutic activity. There have been algorithms for that purpose.

We can work on your protein engineering projects with combinatorial methods, and screen the designed libraries in an automated fashion for both efficiency and accuracy.

References:
1. Allen BD, Nisthal A, Mayo SL. Experimental library screening demonstrates the successful application of computational protein design to large structural ensembles. Proc Natl Acad Sci U S A. 2010 Nov 16; 107(46):19838-43.


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