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      High thermodynamic stability of parametrically designed helical bundles.

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          Abstract

          We describe a procedure for designing proteins with backbones produced by varying the parameters in the Crick coiled coil-generating equations. Combinatorial design calculations identify low-energy sequences for alternative helix supercoil arrangements, and the helices in the lowest-energy arrangements are connected by loop building. We design an antiparallel monomeric untwisted three-helix bundle with 80-residue helices, an antiparallel monomeric right-handed four-helix bundle, and a pentameric parallel left-handed five-helix bundle. The designed proteins are extremely stable (extrapolated ΔGfold > 60 kilocalories per mole), and their crystal structures are close to those of the design models with nearly identical core packing between the helices. The approach enables the custom design of hyperstable proteins with fine-tuned geometries for a wide range of applications.

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          Most cited references 24

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          Toward high-resolution de novo structure prediction for small proteins.

          The prediction of protein structure from amino acid sequence is a grand challenge of computational molecular biology. By using a combination of improved low- and high-resolution conformational sampling methods, improved atomically detailed potential functions that capture the jigsaw puzzle-like packing of protein cores, and high-performance computing, high-resolution structure prediction (<1.5 angstroms) can be achieved for small protein domains (<85 residues). The primary bottleneck to consistent high-resolution prediction appears to be conformational sampling.
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            Is Open Access

            RosettaScripts: A Scripting Language Interface to the Rosetta Macromolecular Modeling Suite

            Macromolecular modeling and design are increasingly useful in basic research, biotechnology, and teaching. However, the absence of a user-friendly modeling framework that provides access to a wide range of modeling capabilities is hampering the wider adoption of computational methods by non-experts. RosettaScripts is an XML-like language for specifying modeling tasks in the Rosetta framework. RosettaScripts provides access to protocol-level functionalities, such as rigid-body docking and sequence redesign, and allows fast testing and deployment of complex protocols without need for modifying or recompiling the underlying C++ code. We illustrate these capabilities with RosettaScripts protocols for the stabilization of proteins, the generation of computationally constrained libraries for experimental selection of higher-affinity binding proteins, loop remodeling, small-molecule ligand docking, design of ligand-binding proteins, and specificity redesign in DNA-binding proteins.
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              ProTherm and ProNIT: thermodynamic databases for proteins and protein–nucleic acid interactions

              ProTherm and ProNIT are two thermodynamic databases that contain experimentally determined thermodynamic parameters of protein stability and protein–nucleic acid interactions, respectively. The current versions of both the databases have considerably increased the total number of entries and enhanced search interface with added new fields, improved search, display and sorting options. As on September 2005, ProTherm release 5.0 contains 17 113 entries from 771 proteins, retrieved from 1497 scientific articles (∼20% increase in data from the previous version). ProNIT release 2.0 contains 4900 entries from 273 research articles, representing 158 proteins. Both databases can be queried using WWW interfaces. Both quick search and advanced search are provided on this web page to facilitate easy retrieval and display of the data from these databases. ProTherm is freely available online at and ProNIT at .
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                Author and article information

                Journal
                Science
                Science (New York, N.Y.)
                1095-9203
                0036-8075
                Oct 24 2014
                : 346
                : 6208
                Affiliations
                [1 ] Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
                [2 ] Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50/3, 8010-Graz, Austria.
                [3 ] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
                [4 ] Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
                [5 ] Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
                [6 ] Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. dabaker@u.washington.edu.
                Article
                346/6208/481 EMS65445
                10.1126/science.1257481
                4612401
                25342806
                4bfff98a-9686-43cd-8626-ede7c1c9530b
                Copyright © 2014, American Association for the Advancement of Science.

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