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11.01.2016 09:24 Von: S Danes

Successful de novo protein design

Joint authorship for Kaspar Feldmeier in Nature Chemical Biology


“It is my belief that as we advance with our knowledge about cells, their components' formation and interactions between those components, we cross the point where a single human can understand our model of a cell and its ingredients in every aspect. If we want to make predictions in such an environment we often depend on computer algorithms and mathematics. It is this cross-talk between mathematics and biology I am most interested in.” In this way Kaspar Feldmeier describes the fascination that led him to begin his PhD in the field of protein folding prediction and protein design.

 

With a Diplom in Biology from the University of Tübingen and studies in Mathematics carried out in parallel, Kaspar is well-qualified for his chosen field, and joined the laboratory of Birte Höcker at the MPI for Developmental Biology as an IMPRS doctoral candidate in 2011.

 

Since then, Kaspar has taken up the challenge of designing a novel protease by inserting the catalytic motif of serine proteases into an existing protein with no natural protease activity. This task is aided by an algorithm called ScaffoldSelection developed in the Höcker lab, which selects candidate proteins with a suitable geometry for insertion of the new motif and helps identify the best insertion site1.

 

In parallel, Kaspar has worked on one of the most widespread and versatile protein folds: the TIM-barrel fold. This fold structure is found in all living organisms, from prokaryotes and archaea to eukaryotes, and is one of the most common folds found in enzymes. Due to its versatility and high stability, the fold has been extensively utilized as a scaffold for enzyme design, leading to the idea to design a TIM-barrel de novo. In a collaboration with the University of Washington, Seattle, Kaspar and colleagues have succeeded in the de novo design of a four-fold symmetric TIM-barrel protein, reported in Nature Chemical Biology2. The sequence of the novel protein is shown to be distant from other naturally occurring TIM-barrel superfamilies, suggesting it should be possible to design further de novo TIM barrels for use in custom-made enzymes. Read more about the significance of this work in the accompanying News and Views.

 

For a general overview of the field, try this review by Kaspar Feldmeier and Birte Hocker3.

 

1  Stiel AC, Feldmeier K, Höcker B. (2014) Identification of protein scaffolds for enzyme design using scaffold selection. Methods Mol Biol.  1216, 183-96.

2 Huang PS, Feldmeier K, Parmeggiani F, Fernandez Velasco DA, Höcker B, Baker D (2015).  De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy. Nat Chem Biol. 1, 29-34.

3 Feldmeier K & Hocker B (2013) Computational protein design of ligand binding and catalysis. Curr Opin Chem Biol 17, 929-33.