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Kuhlman rosetta

Rebecca F Alford, Andrew Leaver-Fay, Jeliazko R Jeliazkov, Matthew J O'Meara, Frank P DiMaio, Hahnbeom Park, Maxim V Shapovalov, P Douglas Renfrew, Vikram K Mulligan, Kalli Kappel, Jason W Labonte, Michael S Pacella, Richard Bonneau, Philip Bradley, Roland L Dunbrack, Rhiju Das, David Baker, Brian Kuhlman, Tanja Kortemme, Jeffrey J Gray
Over the past decade, the Rosetta biomolecular modeling suite has informed diverse biological questions and engineering challenges ranging from interpretation of low-resolution structural data to design of nanomaterials, protein therapeutics, and vaccines. Central to Rosetta's success is the energy function: a model parametrized from small-molecule and X-ray crystal structure data used to approximate the energy associated with each biomolecule conformation. This paper describes the mathematical models and physical concepts that underlie the latest Rosetta energy function, called the Rosetta Energy Function 2015 (REF15)...
June 13, 2017: Journal of Chemical Theory and Computation
Sharon L Guffy, Bryan S Der, Brian Kuhlman
Structure-based protein design tests our understanding of the minimal determinants of protein structure and function. Previous studies have demonstrated that placing zinc binding amino acids (His, Glu, Asp or Cys) near each other in a folded protein in an arrangement predicted to be tetrahedral is often sufficient to achieve binding to zinc. However, few designs have been characterized with high-resolution structures. Here, we use X-ray crystallography, binding studies and mutation analysis to evaluate three alternative strategies for designing zinc binding sites with the molecular modeling program Rosetta...
August 2016: Protein Engineering, Design & Selection: PEDS
Joseph S Harrison, Tim M Jacobs, Kevin Houlihan, Koenraad Van Doorslaer, Brian Kuhlman
This article provides information to support the database article titled "UbSRD: The Ubiquitin Structural Relational Database" (Harrison et al., 2015) [1] . The ubiquitin-like homology fold (UBL) represents a large family that encompasses both post-translational modifications, like ubiquitin (UBQ) and SUMO, and functional domains on many biologically important proteins like Parkin, UHRF1 (ubiquitin-like with PDB and RING finger domains-1), and Usp7 (ubiquitin-specific protease-7) (Zhang et al., 2015; Rothbart et al...
December 2015: Data in Brief
Doo Nam Kim, Timothy M Jacobs, Brian Kuhlman
β-sheets often have one face packed against the core of the protein and the other facing solvent. Mutational studies have indicated that the solvent-facing residues can contribute significantly to protein stability, and that the preferred amino acid at each sequence position is dependent on the precise structure of the protein backbone and the identity of the neighboring amino acids. This suggests that the most advantageous methods for designing β-sheet surfaces will be approaches that take into account the multiple energetic factors at play including side chain rotamer preferences, van der Waals forces, electrostatics, and desolvation effects...
March 2016: Protein Science: a Publication of the Protein Society
Joseph S Harrison, Tim M Jacobs, Kevin Houlihan, Koenraad Van Doorslaer, Brian Kuhlman
The structurally defined ubiquitin-like homology fold (UBL) can engage in several unique protein-protein interactions and many of these complexes have been characterized with high-resolution techniques. Using Rosetta's structural classification tools, we have created the Ubiquitin Structural Relational Database (UbSRD), an SQL database of features for all 509 UBL-containing structures in the PDB, allowing users to browse these structures by protein-protein interaction and providing a platform for quantitative analysis of structural features...
February 22, 2016: Journal of Molecular Biology
Luis Martinez-Rodriguez, Ozgün Erdogan, Mariel Jimenez-Rodriguez, Katiria Gonzalez-Rivera, Tishan Williams, Li Li, Violetta Weinreb, Martha Collier, Srinivas Niranj Chandrasekaran, Xavier Ambroggio, Brian Kuhlman, Charles W Carter
Aminoacyl-tRNA synthetases (aaRS) catalyze both chemical steps that translate the universal genetic code. Rodin and Ohno offered an explanation for the existence of two aaRS classes, observing that codons for the most highly conserved Class I active-site residues are anticodons for corresponding Class II active-site residues. They proposed that the two classes arose simultaneously, by translation of opposite strands from the same gene. We have characterized wild-type 46-residue peptides containing ATP-binding sites of Class I and II synthetases and those coded by a gene designed by Rosetta to encode the corresponding peptides on opposite strands...
August 7, 2015: Journal of Biological Chemistry
Matthew J O'Meara, Andrew Leaver-Fay, Michael D Tyka, Amelie Stein, Kevin Houlihan, Frank DiMaio, Philip Bradley, Tanja Kortemme, David Baker, Jack Snoeyink, Brian Kuhlman
Interactions between polar atoms are challenging to model because at very short ranges they form hydrogen bonds (H-bonds) that are partially covalent in character and exhibit strong orientation preferences; at longer ranges the orientation preferences are lost, but significant electrostatic interactions between charged and partially charged atoms remain. To simultaneously model these two types of behavior, we refined an orientation dependent model of hydrogen bonds [Kortemme et al. J. Mol. Biol. 2003, 326, 1239] used by the molecular modeling program Rosetta and then combined it with a distance-dependent Coulomb model of electrostatics...
February 10, 2015: Journal of Chemical Theory and Computation
Grant S Murphy, Bharatwaj Sathyamoorthy, Bryan S Der, Mischa C Machius, Surya V Pulavarti, Thomas Szyperski, Brian Kuhlman
The de novo design of proteins is a rigorous test of our understanding of the key determinants of protein structure. The helix bundle is an interesting de novo design model system due to the diverse topologies that can be generated from a few simple α-helices. Previously, noncomputational studies demonstrated that connecting amphipathic helices together with short loops can sometimes generate helix bundle proteins, regardless of the bundle's exact sequence. However, using such methods, the precise positions of helices and side chains cannot be predetermined...
April 2015: Protein Science: a Publication of the Protein Society
Charles W Carter, Li Li, Violetta Weinreb, Martha Collier, Katiria Gonzalez-Rivera, Mariel Jimenez-Rodriguez, Ozgün Erdogan, Brian Kuhlman, Xavier Ambroggio, Tishan Williams, S Niranj Chandrasekharan
BACKGROUND: Because amino acid activation is rate-limiting for uncatalyzed protein synthesis, it is a key puzzle in understanding the origin of the genetic code. Two unrelated classes (I and II) of contemporary aminoacyl-tRNA synthetases (aaRS) now translate the code. Observing that codons for the most highly conserved, Class I catalytic peptides, when read in the reverse direction, are very nearly anticodons for Class II defining catalytic peptides, Rodin and Ohno proposed that the two superfamilies descended from opposite strands of the same ancestral gene...
June 14, 2014: Biology Direct
Kevin Drew, P Douglas Renfrew, Timothy W Craven, Glenn L Butterfoss, Fang-Chieh Chou, Sergey Lyskov, Brooke N Bullock, Andrew Watkins, Jason W Labonte, Michael Pacella, Krishna Praneeth Kilambi, Andrew Leaver-Fay, Brian Kuhlman, Jeffrey J Gray, Philip Bradley, Kent Kirshenbaum, Paramjit S Arora, Rhiju Das, Richard Bonneau
Peptidomimetics are classes of molecules that mimic structural and functional attributes of polypeptides. Peptidomimetic oligomers can frequently be synthesized using efficient solid phase synthesis procedures similar to peptide synthesis. Conformationally ordered peptidomimetic oligomers are finding broad applications for molecular recognition and for inhibiting protein-protein interactions. One critical limitation is the limited set of design tools for identifying oligomer sequences that can adopt desired conformations...
2013: PloS One
Bryan S Der, Christien Kluwe, Aleksandr E Miklos, Ron Jacak, Sergey Lyskov, Jeffrey J Gray, George Georgiou, Andrew D Ellington, Brian Kuhlman
Reengineering protein surfaces to exhibit high net charge, referred to as "supercharging", can improve reversibility of unfolding by preventing aggregation of partially unfolded states. Incorporation of charged side chains should be optimized while considering structural and energetic consequences, as numerous mutations and accumulation of like-charges can also destabilize the native state. A previously demonstrated approach deterministically mutates flexible polar residues (amino acids DERKNQ) with the fewest average neighboring atoms per side chain atom (AvNAPSA)...
2013: PloS One
Sergey Lyskov, Fang-Chieh Chou, Shane Ó Conchúir, Bryan S Der, Kevin Drew, Daisuke Kuroda, Jianqing Xu, Brian D Weitzner, P Douglas Renfrew, Parin Sripakdeevong, Benjamin Borgo, James J Havranek, Brian Kuhlman, Tanja Kortemme, Richard Bonneau, Jeffrey J Gray, Rhiju Das
The Rosetta molecular modeling software package provides experimentally tested and rapidly evolving tools for the 3D structure prediction and high-resolution design of proteins, nucleic acids, and a growing number of non-natural polymers. Despite its free availability to academic users and improving documentation, use of Rosetta has largely remained confined to developers and their immediate collaborators due to the code's difficulty of use, the requirement for large computational resources, and the unavailability of servers for most of the Rosetta applications...
2013: PloS One
Bryan S Der, Ramesh K Jha, Raamesh K Jha, Steven M Lewis, Peter M Thompson, Gurkan Guntas, Brian Kuhlman
We computationally designed a de novo protein-protein interaction between wild-type ubiquitin and a redesigned scaffold. Our strategy was to incorporate zinc at the designed interface to promote affinity and orientation specificity. A large set of monomeric scaffold surfaces were computationally engineered with three-residue zinc coordination sites, and the ubiquitin residue H68 was docked to the open coordination site to complete a tetrahedral zinc site. This single coordination bond was intended as a hotspot and polar interaction for ubiquitin binding, and surrounding residues on the scaffold were optimized primarily as hydrophobic residues using a rotamer-based sequence design protocol in Rosetta...
July 2013: Proteins
Andrew Leaver-Fay, Matthew J O'Meara, Mike Tyka, Ron Jacak, Yifan Song, Elizabeth H Kellogg, James Thompson, Ian W Davis, Roland A Pache, Sergey Lyskov, Jeffrey J Gray, Tanja Kortemme, Jane S Richardson, James J Havranek, Jack Snoeyink, David Baker, Brian Kuhlman
Accurate energy functions are critical to macromolecular modeling and design. We describe new tools for identifying inaccuracies in energy functions and guiding their improvement, and illustrate the application of these tools to the improvement of the Rosetta energy function. The feature analysis tool identifies discrepancies between structures deposited in the PDB and low-energy structures generated by Rosetta; these likely arise from inaccuracies in the energy function. The optE tool optimizes the weights on the different components of the energy function by maximizing the recapitulation of a wide range of experimental observations...
2013: Methods in Enzymology
Jun Zhang, Steven M Lewis, Brian Kuhlman, Andrew L Lee
The family of membrane-associated guanylate kinase (MAGUK) scaffold proteins comprises members that function at neuronal synapses, tight junctions, immunological synapses, and neutrophil membranes. Through their multiple domains, MAGUKs organize events of signal transduction, cell adhesion, and molecular trafficking. Here, we use nuclear magnetic resonance, small-angle X-ray scattering, and Rosetta modeling to reveal the structural preferences and interdomain dynamics of the MAGUK core (PDZ3-SH3-guanylate kinase) from postsynaptic density-95 (PSD-95), the best known MAUGK...
March 5, 2013: Structure
P Benjamin Stranges, Brian Kuhlman
The accurate design of new protein-protein interactions is a longstanding goal of computational protein design. However, most computationally designed interfaces fail to form experimentally. This investigation compares five previously described successful de novo interface designs with 158 failures. Both sets of proteins were designed with the molecular modeling program Rosetta. Designs were considered a success if a high-resolution crystal structure of the complex closely matched the design model and the equilibrium dissociation constant for binding was less than 10 μM...
January 2013: Protein Science: a Publication of the Protein Society
Aleksandr E Miklos, Christien Kluwe, Bryan S Der, Supriya Pai, Aroop Sircar, Randall A Hughes, Monica Berrondo, Jianqing Xu, Vlad Codrea, Patricia E Buckley, Alena M Calm, Heather S Welsh, Candice R Warner, Melody A Zacharko, James P Carney, Jeffrey J Gray, George Georgiou, Brian Kuhlman, Andrew D Ellington
Mutation of surface residues to charged amino acids increases resistance to aggregation and can enable reversible unfolding. We have developed a protocol using the Rosetta computational design package that "supercharges" proteins while considering the energetic implications of each mutation. Using a homology model, a single-chain variable fragment antibody was designed that has a markedly enhanced resistance to thermal inactivation and displays an unanticipated ≈30-fold improvement in affinity. Such supercharged antibodies should prove useful for assays in resource-limited settings and for developing reagents with improved shelf lives...
April 20, 2012: Chemistry & Biology
P Douglas Renfrew, Eun Jung Choi, Richard Bonneau, Brian Kuhlman
Noncanonical amino acids (NCAAs) can be used in a variety of protein design contexts. For example, they can be used in place of the canonical amino acids (CAAs) to improve the biophysical properties of peptides that target protein interfaces. We describe the incorporation of 114 NCAAs into the protein-modeling suite Rosetta. We describe our methods for building backbone dependent rotamer libraries and the parameterization and construction of a scoring function that can be used to score NCAA containing peptides and proteins...
2012: PloS One
Ron Jacak, Andrew Leaver-Fay, Brian Kuhlman
De novo protein design requires the identification of amino-acid sequences that favor the target-folded conformation and are soluble in water. One strategy for promoting solubility is to disallow hydrophobic residues on the protein surface during design. However, naturally occurring proteins often have hydrophobic amino acids on their surface that contribute to protein stability via the partial burial of hydrophobic surface area or play a key role in the formation of protein-protein interactions. A less restrictive approach for surface design that is used by the modeling program Rosetta is to parameterize the energy function so that the number of hydrophobic amino acids designed on the protein surface is similar to what is observed in naturally occurring monomeric proteins...
March 2012: Proteins
Bryan S Der, Mischa Machius, Michael J Miley, Jeffrey L Mills, Thomas Szyperski, Brian Kuhlman
Computationally designing protein-protein interactions with high affinity and desired orientation is a challenging task. Incorporating metal-binding sites at the target interface may be one approach for increasing affinity and specifying the binding mode, thereby improving robustness of designed interactions for use as tools in basic research as well as in applications from biotechnology to medicine. Here we describe a Rosetta-based approach for the rational design of a protein monomer to form a zinc-mediated, symmetric homodimer...
January 11, 2012: Journal of the American Chemical Society
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