Fast, cheap and out of control - Insights into thermodynamic and informatic constraints on natural protein sequences from de novo protein design

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Abstract

The accumulated results of thirty years of rational and computational de novo protein design have taught us important lessons about the stability, information content, and evolution of natural proteins. First, de novo protein design has complicated the assertion that biological function is equivalent to biological structure - demonstrating the capacity to abstract active sites from natural contexts and paste them into non-native topologies without loss of function. The structure-function relationship has thus been revealed to be either a generality or strictly true only in a local sense. Second, the simplification to "maquette" topologies carried out by rational protein design also has demonstrated that even sophisticated functions such as conformational switching, cooperative ligand binding, and light-activated electron transfer can be achieved with low-information design approaches. This is because for simple topologies the functional footprint in sequence space is enormous and easily exceeds the number of structures which could have possibly existed in the history of life on Earth. Finally, the pervasiveness of extraordinary stability in designed proteins challenges accepted models for the "marginal stability" of natural proteins, suggesting that there must be a selection pressure against highly stable proteins. This can be explained using recent theories which relate non-equilibrium thermodynamics and self-replication. This article is part of a Special Issue entitled Biodesign for Bioenergetics - The design and engineering of electronc transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson.

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Brisendine, J. M., & Koder, R. L. (2016). Fast, cheap and out of control - Insights into thermodynamic and informatic constraints on natural protein sequences from de novo protein design. Biochimica et Biophysica Acta - Bioenergetics, 1857(5), 485–492. https://doi.org/10.1016/j.bbabio.2015.10.002

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