Protein structure prediction using Rosetta in CASP12 Ovchinnikov, Sergey; Park, Hahnbeom; Kim, David E. ...
Proteins, structure, function, and bioinformatics,
March 2018, Letnik:
86, Številka:
S1
Journal Article
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We describe several notable aspects of our structure predictions using Rosetta in CASP12 in the free modeling (FM) and refinement (TR) categories. First, we had previously generated (and published) ...models for most large protein families lacking experimentally determined structures using Rosetta guided by co‐evolution based contact predictions, and for several targets these models proved better starting points for comparative modeling than any known crystal structure—our model database thus starts to fulfill one of the goals of the original protein structure initiative. Second, while our “human” group simply submitted ROBETTA models for most targets, for six targets expert intervention improved predictions considerably; the largest improvement was for T0886 where we correctly parsed two discontinuous domains guided by predicted contact maps to accurately identify a structural homolog of the same fold. Third, Rosetta all atom refinement followed by MD simulations led to consistent but small improvements when starting models were close to the native structure, and larger but less consistent improvements when starting models were further away.
Proteins fold to their lowest free-energy structures, and hence the most straightforward way to increase the accuracy of a partially incorrect protein structure model is to search for the ...lowest-energy nearby structure. This direct approach has met with little success for two reasons: first, energy function inaccuracies can lead to false energy minima, resulting in model degradation rather than improvement; and second, even with an accurate energy function, the search problem is formidable because the energy only drops considerably in the immediate vicinity of the global minimum, and there are a very large number of degrees of freedom. Here we describe a large-scale energy optimization-based refinement method that incorporates advances in both search and energy function accuracy that can substantially improve the accuracy of low-resolution homology models. The method refined low-resolution homology models into correct folds for 50 of 84 diverse protein families and generated improved models in recent blind structure prediction experiments. Analyses of the basis for these improvements reveal contributions from both the improvements in conformational sampling techniques and the energy function.
The cytochrome bd oxidases are terminal oxidases that are present in bacteria and archaea. They reduce molecular oxygen (dioxygen) to water, avoiding the production of reactive oxygen species. In ...addition to their contribution to the proton motive force, they mediate viability under oxygen-related stress conditions and confer tolerance to nitric oxide, thus contributing to the virulence of pathogenic bacteria. Here we present the atomic structure of the bd oxidase from Geobacillus thermodenitrificans, revealing a pseudosymmetrical subunit fold. The arrangement and order of the heme cofactors support the conclusions from spectroscopic measurements that the cleavage of the dioxygen bond may be mechanistically similar to that in the heme-copper–containing oxidases, even though the structures are completely different.
Members of the Zrt and Irt protein (ZIP) family are a central participant in transition metal homeostasis as they function to increase the cytosolic concentration of zinc and/or iron. However, the ...lack of a crystal structure hinders elucidation of the molecular mechanism of ZIP proteins. Here, we employed GREMLIN, a co-evolution-based contact prediction approach in conjunction with the Rosetta structure prediction program to construct a structural model of the human (h) ZIP4 transporter. The predicted contact data are best fit by modeling hZIP4 as a dimer. Mutagenesis of residues that comprise a central putative hZIP4 transmembrane transition metal coordination site in the structural model alter the kinetics and specificity of hZIP4. Comparison of the hZIP4 dimer model to all known membrane protein structures identifies the 12-transmembrane monomeric Piriformospora indica phosphate transporter (PiPT), a member of the major facilitator superfamily (MFS), as a likely structural homolog.
ZIP transporters increase the cytosolic concentration of first row transition metals.
We have developed a structural model of hZIP4 by combining protein prediction methods with in situ experiments.
Analysis of our experiments provides insight into the permeation pathway of hZIP4.
Comparison of this model to membrane transporter crystal structures provides a structural linkage to MFS proteins.
The prediction of the structures of proteins without detectable sequence similarity to any protein of known structure remains an outstanding scientific challenge. Here we report significant progress ...in this area. We first describe de novo blind structure predictions of unprecendented accuracy we made for two proteins in large families in the recent CASP11 blind test of protein structure prediction methods by incorporating residue-residue co-evolution information in the Rosetta structure prediction program. We then describe the use of this method to generate structure models for 58 of the 121 large protein families in prokaryotes for which three-dimensional structures are not available. These models, which are posted online for public access, provide structural information for the over 400,000 proteins belonging to the 58 families and suggest hypotheses about mechanism for the subset for which the function is known, and hypotheses about function for the remainder.
We study quench dynamics and defects formation in the one-dimensional quantum Ising chain in a time-dependent transverse magnetic field, given by a semi-infinite pulse and as the pulse of the finite ...width. The system’s final state depends on the quench time and pulse amplitude, resulting in the emergence of topological defects, and consists of a mixture of ground and excited states. We obtain a new analytical expression, generalizing the Landau–Zener (LZ) and adiabatic-impulse (AI) approximation formulas for the asymptotic probability of remaining in the ground state. We show that our theoretical predictions are in good agreement with the results of the numerical simulations, even when the LZ and AI approximations fail.
Graphic abstract
Deciphering the relationship between a gene and its genomic context is fundamental to understanding and engineering biological systems. Machine learning has shown promise in learning latent ...relationships underlying the sequence-structure-function paradigm from massive protein sequence datasets. However, to date, limited attempts have been made in extending this continuum to include higher order genomic context information. Evolutionary processes dictate the specificity of genomic contexts in which a gene is found across phylogenetic distances, and these emergent genomic patterns can be leveraged to uncover functional relationships between gene products. Here, we train a genomic language model (gLM) on millions of metagenomic scaffolds to learn the latent functional and regulatory relationships between genes. gLM learns contextualized protein embeddings that capture the genomic context as well as the protein sequence itself, and encode biologically meaningful and functionally relevant information (e.g. enzymatic function, taxonomy). Our analysis of the attention patterns demonstrates that gLM is learning co-regulated functional modules (i.e. operons). Our findings illustrate that gLM's unsupervised deep learning of the metagenomic corpus is an effective and promising approach to encode functional semantics and regulatory syntax of genes in their genomic contexts and uncover complex relationships between genes in a genomic region.
Electronic structure and magnetic properties of Fe3Se4 are calculated using the density functional approach. Due to the metallic properties, magnetic moments of the iron atoms in two nonequivalent ...positions in the unit cell are different from ionic values for Fe3+ and Fe2+ and are equal to M1=2.071μB and M2=−2.042μB, making the system ferrimagnetic. The total magnetic moment for the unit cell is 2.135μB. Under isotropic compression, the total magnetic moment decreases non-monotonically and correlates with the non-monotonic dependence of the density of states at the Fermi level N(EF). For 7% compression, the magnetic order changes from the ferrimagnetic to the ferromagnetic. At 14% compression, the magnetic order disappears and the total magnetic moment becomes zero, leaving the system in a paramagnetic state. This compression corresponds to the pressure of 114 GPa. The magnetic ordering changes faster upon application of an isotropic external pressure due to the sizeable anisotropy of the chemical bondings in Fe3Se4. The ferrimagnetic and paramagnetic states occur under pressures of 5.0 and 8.0 GPa, respectively. The system remains in the metallic state for all values of compression.
The structural, magnetic, electrical, and dilatation properties of the rare-earth NdCoO3 and SmCoO3 cobaltites were investigated. Their comparative analysis was carried out and the effect of ...multiplicity fluctuations on physical properties of the studied cobaltites was considered. Correlations between the spin state change of cobalt ions and the temperature dependence anomalies of the lattice parameters, magnetic susceptibility, volume thermal expansion coefficient, and electrical resistance have been revealed. A comparison of the results with well-studied GdCoO3 allows one to single out both the general tendencies inherent in all rare-earth cobaltites taking into account the lanthanide contraction and peculiar properties of the samples containing Nd and Sm.
CuO atomic thin monolayer (mlCuO) was synthesized recently. Interest in the mlCuO is based on its close relation to CuO2 layers in typical high temperature cuprate superconductors. Here, we present ...the calculation of the band structure, the density of states and the Fermi surface of the flat mlCuO as well as the corrugated mlCuO within the density functional theory (DFT) in the generalized gradient approximation (GGA). In the flat mlCuO, the Cu-3dx2-y2 band crosses the Fermi level, while the Cu-3dxz,yz hybridized band is located just below it. The corrugation leads to a significant shift of the Cu-3dxz,yz hybridized band down in energy and a degeneracy lifting for the Cu-3dx2-y2 bands. Corrugated mlCuO is more energetically favorable than the flat one. In addition, we compared the electronic structure of the considered CuO monolayers with bulk CuO systems. We also investigated the influence of a crystal lattice strain (which might occur on some interfaces) on the electronic structure of both mlCuO and determined the critical strains of topological Lifshitz transitions. Finally, we proposed a number of different minimal models for the flat and the corrugated mlCuO using projections onto different Wannier functions basis sets and obtained the corresponding Hamiltonian matrix elements in a real space.
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