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Miniprotein Design: Past, Present and Prospects

Research output: Contribution to journalSpecial issue

Original languageEnglish
JournalAccounts of Chemical Research
Early online date23 Aug 2017
DOIs
StateE-pub ahead of print - 23 Aug 2017

Abstract

The design and study of miniproteins – that is, polypeptide chains < 40 amino acids in length that adopt defined and stable 3D structures – is resurgent. Miniproteins offer possibilities for reducing the complexity of larger proteins, and so present new routes to studying sequence-to-structure and sequence-to-stability relationships in proteins generally. They also provide modules for protein design by pieces and, with this, prospects for building more-complex or even entirely new protein structures. In addition, miniproteins are useful scaffolds for templating functional domains; e.g., those involved in protein-protein interactions, catalysis, and biomolecular binding, leading to potential applications in biotechnology and medicine. Here we select examples from almost four decades of miniprotein design, development and dissection. Simply because of the word limit for these Accounts, we focus on miniproteins that are cooperatively folded monomers in solution and not stabilized by cross-linking or metal binding. In these cases, the optimization of non-covalent interactions is even more critical for the maintenance of the folded states than in larger proteins. Our chronology and catalogue highlights themes in miniproteins, which we explore further and begin to put on a firmer footing through an analysis of the miniprotein structures that have been deposited in the Protein Data Bank (PDB) thus far. Specifically, and compared with larger proteins, miniproteins generally have a lower proportion of residues in regular secondary structure elements ( helices,  strands, and polyproline II helices) and, concomitantly, more residues in well-structured loops. This allows distortions of the backbone enabling mini hydrophobic cores to be made. This also contrasts with larger proteins, which can achieve hydrophobic cores through tertiary contacts between distant regions of sequence. On average, miniproteins have a higher proportion of aromatic residues than larger proteins, and specifically electron-rich Trp and/or Tyr, which are often found in combination with Pro and Arg to render networks of CH–π or cation–π interactions. Miniproteins also have a higher proportion of the long-chain charged amino acids (Arg, Glu, and Lys), which presumably reflects salt-bridge formation and their greater surface area-to-volume ratio. Together, these amino-acid preferences appear to support greater densities of non-covalent interactions in miniproteins compared with larger proteins. We anticipate that with recent developments such as parametric protein design, it will become increasingly routine to use computation to generate and evaluate models for miniproteins in silico ahead of experimental studies. This could include accessing new structures comprising secondary structure elements linked in previously unseen configurations. The improved understanding of the non-covalent interactions that stabilize the folded states of such miniproteins that we are witnessing through both in-depth bioinformatics analyses and experimental testing will feed these computational protein designs. With this in mind, we can expect a new and exciting era for miniprotein design, study and application.

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via at ACS Publications http://pubs.acs.org/doi/abs/10.1021/acs.accounts.7b00186. Please refer to any applicable terms of use of the publisher.

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