Contents

The Core Repacking Problem 314

Predicting Native Protein Core Sequences 314

Early Core Designs (cro, ubiquitin, and T4 lysozyme) 315

Overcoming Limitations: The Rotamer Library 317

Overcoming Limitations: Circumventing the Fixed Backbone 318

Full Repacks and Surface Design 320

Hydrogen Bonding and Polar Residues in the Core 322

Altering Protein Folds 322

Experimentally Evaluating Success 323

Conclusion 324

References 324

In the structural biology of proteins, the dogma is that sequence defines structure, which in turn defines function. In order to design functional proteins, therefore, the first step is to fill in the gap between sequence and structure; if a sequence can be designed for an arbitrary structure, then function should follow. To this end, many design algorithms have focused on the ability to reliably predict sequences that can fold, specifically into a desired tertiary structure. This has proven to be a robust test of our understanding of the forces that govern protein folding.

More than a test, however, protein design has been able to increase the stability of biological proteins, adjust their solubility and oligomerization behavior, and in one case, produce an entirely novel fold. At the same time, design of specific scaffolds and structures is still not trivial, and most successes have been restricted to small scaffolds, subsets of larger proteins, or simple topologies such as helical bundles. This barrier is primarily due to problems with force-field accuracy, the ability of search algorithms to find physically reasonable solutions, and the need to make approximations and compromises in both due to limited computational resources.

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