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J Struct Biol. 2018 Jul;203(1):54-61. doi: 10.1016/j.jsb.2018.02.004. Epub 2018 Feb 14.

Combining Rosetta with molecular dynamics (MD): A benchmark of the MD-based ensemble protein design.

Author information

1
Laboratory of Structural Bioinformatics, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland; Laboratory of Bioinformatics, Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland.
2
Laboratory of Bioinformatics, Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland.
3
Laboratory of Structural Bioinformatics, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland. Electronic address: s.dunin-horkawicz@cent.uw.edu.pl.

Abstract

Computational protein design is a set of procedures for computing amino acid sequences that will fold into a specified structure. Rosetta Design, a commonly used software for protein design, allows for the effective identification of sequences compatible with a given backbone structure, while molecular dynamics (MD) simulations can thoroughly sample near-native conformations. We benchmarked a procedure in which Rosetta design is started on MD-derived structural ensembles and showed that such a combined approach generates 20-30% more diverse sequences than currently available methods with only a slight increase in computation time. Importantly, the increase in diversity is achieved without a loss in the quality of the designed sequences assessed by their resemblance to natural sequences. We demonstrate that the MD-based procedure is also applicable to de novo design tasks started from backbone structures without any sequence information. In addition, we implemented a protocol that can be used to assess the stability of designed models and to select the best candidates for experimental validation. In sum our results demonstrate that the MD ensemble-based flexible backbone design can be a viable method for protein design, especially for tasks that require a large pool of diverse sequences.

KEYWORDS:

Backbone flexibility; Molecular dynamics; Protein design; Rosetta

PMID:
29454111
DOI:
10.1016/j.jsb.2018.02.004
[Indexed for MEDLINE]

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