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A major challenge of computational protein design is the creation of novel proteins with arbitrarily chosen three-dimensional structures. Here, we used a general computational strategy that iterates between sequence design and structure prediction to design a 93-residue alpha/beta protein called Top7 with a novel sequence and topology. Top7 was found(More)
Eukaryotes and archaea use two sets of specialized ribonucleoproteins (RNPs) to carry out sequence-specific methylation and pseudouridylation of RNA, the two most abundant types of modifications of cellular RNAs. In eukaryotes, these protein-RNA complexes localize to the nucleolus and are called small nucleolar RNPs (snoRNPs), while in archaea they are(More)
RNA-binding proteins play many essential roles in the regulation of gene expression in the cell. Despite the significant increase in the number of structures for RNA-protein complexes in the last few years, the molecular basis of specificity remains unclear even for the best-studied protein families. We have developed a distance and orientation-dependent(More)
Recent efforts to design de novo or redesign the sequence and structure of proteins using computational techniques have met with significant success. Most, if not all, of these computational methodologies attempt to model atomic-level interactions, and hence high-resolution structural characterization of the designed proteins is critical for evaluating the(More)
Phosphorylation of the C-terminal domain (CTD) of RNA polymerase II controls the co-transcriptional assembly of RNA processing and transcription factors. Recruitment relies on conserved CTD-interacting domains (CIDs) that recognize different CTD phosphoisoforms during the transcription cycle, but the molecular basis for their specificity remains unclear. We(More)
  • Alexander L. Watters, Pritilekha Deka, Colin Corrent, David Callender, Gabriele Varani, Tobin Sosnick +1 other
  • 2007
To illuminate the evolutionary pressure acting on the folding free energy landscapes of naturally occurring proteins, we have systematically characterized the folding free energy landscape of Top7, a computationally designed protein lacking an evolutionary history. Stopped-flow kinetics, circular dichroism, and NMR experiments reveal that there are at least(More)
RNA/protein interactions play crucial roles in controlling gene expression. They are becoming important targets for pharmaceutical applications. Due to RNA flexibility and to the strength of electrostatic interactions, standard docking methods are insufficient. We here present a computational method which allows studying the binding of RNA molecules and(More)
RNA-binding proteins (RBPs) perform many essential functions in the post-transcriptional control of gene expression. If we were able to engineer RBPs with new specificity, it would also become possible to develop new tools to control and investigate gene expression pathways. Molecular evolution methods such as phage display have been introduced to achieve(More)
Achieving atomic-level resolution in the computational design of a protein structure remains a challenging problem despite recent progress. Rigorous experimental tests are needed to improve protein design algorithms, yet studies of the structure and dynamics of computationally designed proteins are very few. The NMR structure and backbone dynamics of a(More)
The pharmacological disruption of the interaction between the HIV Tat protein and its cognate transactivation response RNA (TAR) would generate novel anti-viral drugs with a low susceptibility to drug resistance, but efforts to discover ligands with sufficient potency to warrant pharmaceutical development have been unsuccessful. We have previously described(More)