Backbone Flexibility 368

Parameterization of Structures 368

Ensemble Approach 370

Simultaneous Optimization of Sequence and Structure 371

The Future of Flexible-Backbone Protein Design 373

Negative Design 374

Protein-Protein Interactions 375

Explicit Multistate Design 375

Prescreening for Destabilizing Mutations 377

Experimental Approaches 379

Protein Design 379

Experimental Approaches for High-Throughput Design Sampling 381

High-Throughput Protein Fabrication 381

Design and High-Throughput Selection of Computationally Designed

Protein Libraries 382

Gene Assembly 384

Concluding Remarks 385

References 385

With the recent advances in the field of computational protein design, we have seen many successful examples of de novo designs, including novel protein-protein and protein-DNA interactions, as well as enzymes capable of catalyzing novel reactions. However, the rate of success remains low, which suggests that our understanding of the sequence-structure-function relationship is far from complete. There are many formidable challenges that need to be overcome before we can reliably design new protein molecules at will. Here we review three topics that will be important in the future progress of computational protein design: backbone flexibility, negative design, and experimental approaches.

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