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We present a large-scale approach to investigate the functional consequences of sequence variation in a protein. The approach entails the display of hundreds of thousands of protein variants, moderate selection for activity and high-throughput DNA sequencing to quantify the performance of each variant. Using this strategy, we tracked the performance of(More)
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(More)
A long-term aim of computational design is to generate specific protein-protein interactions at desired affinity, specificity, and kinetics. The past three years have seen the first reports on atomically accurate de novo interactions. These were based on advances in design algorithms and the ability to harness high-throughput experimental characterization(More)
that gap junctions play in coordinating tissue and organ Department of Biochemistry ber of genetic conditions in humans and mouse mod-George S. Wise Faculty of Life Sciences els involving the skin, neurodegenerative and develop-Tel-Aviv University mental diseases, and most cases of nonsyndromic Ramat Aviv, 69978 hereditary deafness have been attributed to(More)
A novel sequence-analysis technique for detecting correlated amino acid positions in intermediate-size protein families (50-100 sequences) was developed, and applied to study voltage-dependent gating of potassium channels. Most contemporary methods for detecting amino acid correlations within proteins use very large sets of data, typically comprising(More)
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(More)
The transmembrane (TM) domains of many integral membrane proteins are composed of alpha-helix bundles. Structure determination at high resolution (<4 A) of TM domains is still exceedingly difficult experimentally. Hence, some TM-protein structures have only been solved at intermediate (5-10 A) or low (>10 A) resolutions using, for example, cryo-electron(More)
A challenge in protein-protein docking is to account for the conformational changes in the monomers that occur upon binding. The RosettaDock method, which incorporates sidechain flexibility but keeps the backbone fixed, was found in previous CAPRI rounds (4 and 5) to generate docking models with atomic accuracy, provided that conformational changes were(More)
We describe a general computational method for designing proteins that bind a surface patch of interest on a target macromolecule. Favorable interactions between disembodied amino acid residues and the target surface are identified and used to anchor de novo designed interfaces. The method was used to design proteins that bind a conserved surface patch on(More)
Recently, excitement has surrounded the application of null-hypothesis approaches for identifying evolutionary design principles in biological, technological, and social networks (1–13) and for classifying diverse networks into distinctive superfamilies (2). Here, we argue that the basic method suggested by Milo et al. (1, 2) often has limitations in(More)