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Computer-aided design of functional protein interactions

Abstract

Predictive methods for the computational design of proteins search for amino acid sequences adopting desired structures that perform specific functions. Typically, design of 'function' is formulated as engineering new and altered binding activities into proteins. Progress in the design of functional protein-protein interactions is directed toward engineering proteins to precisely control biological processes by specifically recognizing desired interaction partners while avoiding competitors. The field is aiming for strategies to harness recent advances in high-resolution computational modeling—particularly those exploiting protein conformational variability—to engineer new functions and incorporate many functional requirements simultaneously.

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Figure 1: Concepts for protein interface design.
Figure 2: Sampling concepts in computational protein design.
Figure 3: Dominant contributions to protein design scoring functions.
Figure 4: Structurally characterized designed protein-protein interfaces.
Figure 5: Design of a multi-specific protein-protein interface.

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Acknowledgements

We thank members of the Kortemme group and the Rosetta developers community for many stimulating discussions and important contributions. This work was supported by a CAREER award from the US National Science Foundation (T.K.) and a PhRMA Foundation Predoctoral Fellowship (D.J.M.).

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Correspondence to Tanja Kortemme.

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Mandell, D., Kortemme, T. Computer-aided design of functional protein interactions. Nat Chem Biol 5, 797–807 (2009). https://doi.org/10.1038/nchembio.251

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