The coming of age of de novo protein design

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Abstract

There are 20(200) possible amino-acid sequences for a 200-residue protein, of which the natural evolutionary process has sampled only an infinitesimal subset. De novo protein design explores the full sequence space, guided by the physical principles that underlie protein folding. Computational methodology has advanced to the point that a wide range of structures can be designed from scratch with atomic-level accuracy. Almost all protein engineering so far has involved the modification of naturally occurring proteins; it should now be possible to design new functional proteins from the ground up to tackle current challenges in biomedicine and nanotechnology.

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ROSETTA3: an object-oriented software suite for the simulation and design of macromolecules.

Andrew Leaver-Fay, Michael Tyka, Steven M. Lewis … (2011)

We have recently completed a full re-architecturing of the ROSETTA molecular modeling program, generalizing and expanding its existing functionality. The new architecture enables the rapid prototyping of novel protocols by providing easy-to-use interfaces to powerful tools for molecular modeling. The source code of this rearchitecturing has been released as ROSETTA3 and is freely available for academic use. At the time of its release, it contained 470,000 lines of code. Counting currently unpublished protocols at the time of this writing, the source includes 1,285,000 lines. Its rapid growth is a testament to its ease of use. This chapter describes the requirements for our new architecture, justifies the design decisions, sketches out central classes, and highlights a few of the common tasks that the new software can perform. © 2011 Elsevier Inc. All rights reserved.

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Assembly of protein tertiary structures from fragments with similar local sequences using simulated annealing and Bayesian scoring functions.

K. T. Simons, C Kooperberg, E. Huang … (1997)

We explore the ability of a simple simulated annealing procedure to assemble native-like structures from fragments of unrelated protein structures with similar local sequences using Bayesian scoring functions. Environment and residue pair specific contributions to the scoring functions appear as the first two terms in a series expansion for the residue probability distributions in the protein database; the decoupling of the distance and environment dependencies of the distributions resolves the major problems with current database-derived scoring functions noted by Thomas and Dill. The simulated annealing procedure rapidly and frequently generates native-like structures for small helical proteins and better than random structures for small beta sheet containing proteins. Most of the simulated structures have native-like solvent accessibility and secondary structure patterns, and thus ensembles of these structures provide a particularly challenging set of decoys for evaluating scoring functions. We investigate the effects of multiple sequence information and different types of conformational constraints on the overall performance of the method, and the ability of a variety of recently developed scoring functions to recognize the native-like conformations in the ensembles of simulated structures.

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Assessing the utility of coevolution-based residue-residue contact predictions in a sequence- and structure-rich era.

Hetunandan Kamisetty, Sergey Ovchinnikov, David. Baker (2013)

Recently developed methods have shown considerable promise in predicting residue-residue contacts in protein 3D structures using evolutionary covariance information. However, these methods require large numbers of evolutionarily related sequences to robustly assess the extent of residue covariation, and the larger the protein family, the more likely that contact information is unnecessary because a reasonable model can be built based on the structure of a homolog. Here we describe a method that integrates sequence coevolution and structural context information using a pseudolikelihood approach, allowing more accurate contact predictions from fewer homologous sequences. We rigorously assess the utility of predicted contacts for protein structure prediction using large and representative sequence and structure databases from recent structure prediction experiments. We find that contact predictions are likely to be accurate when the number of aligned sequences (with sequence redundancy reduced to 90%) is greater than five times the length of the protein, and that accurate predictions are likely to be useful for structure modeling if the aligned sequences are more similar to the protein of interest than to the closest homolog of known structure. These conditions are currently met by 422 of the protein families collected in the Pfam database.

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Journal

Title: Nature

Abbreviated Title: Nature

Publisher: Springer Science and Business Media LLC

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Created: September 2016

Publication date (Electronic): September 14 2016

Publication date (Print): September 2016

Volume: 537

Issue: 7620

Pages: 320-327

Article

DOI: 10.1038/nature19946

PubMed ID: 27629638

SO-VID: 1aff17f1-9018-4ac5-879e-3b3e2069c322

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http://www.springer.com/tdm

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The coming of age of de novo protein design

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Abstract

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Arabidopsis genomics

Most cited references 73

ROSETTA3: an object-oriented software suite for the simulation and design of macromolecules.

Assembly of protein tertiary structures from fragments with similar local sequences using simulated annealing and Bayesian scoring functions.

Assessing the utility of coevolution-based residue-residue contact predictions in a sequence- and structure-rich era.

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