444 research outputs found
COPS—a novel workbench for explorations in fold space
The COPS (Classification Of Protein Structures) web server provides access to the complete repertoire of known protein structures and protein structural domains. The COPS classification encodes pairwise structural similarities as quantified metric relationships. The resulting metrical structure is mapped to a hierarchical tree, which is largely equivalent to the structure of a file browser. Exploiting this relationship we implemented the Fold Space Navigator, a tool that makes navigation in fold space as convenient as browsing through a file system. Moreover, pairwise structural similarities among the domains can be visualized and inspected instantaneously. COPS is updated weekly and stays concurrent with the PDB repository. The server also exposes the COPS classification pipeline. Newly determined structures uploaded to the server are chopped into domains, the locations of the new domains in the classification tree are determined, and their neighborhood can be immediately explored through the Fold Space Navigator. The COPS web server is accessible at http://cops.services.came.sbg.ac.at/
Potentials of Mean Force for Protein Structure Prediction Vindicated, Formalized and Generalized
Understanding protein structure is of crucial importance in science, medicine
and biotechnology. For about two decades, knowledge based potentials based on
pairwise distances -- so-called "potentials of mean force" (PMFs) -- have been
center stage in the prediction and design of protein structure and the
simulation of protein folding. However, the validity, scope and limitations of
these potentials are still vigorously debated and disputed, and the optimal
choice of the reference state -- a necessary component of these potentials --
is an unsolved problem. PMFs are loosely justified by analogy to the reversible
work theorem in statistical physics, or by a statistical argument based on a
likelihood function. Both justifications are insightful but leave many
questions unanswered. Here, we show for the first time that PMFs can be seen as
approximations to quantities that do have a rigorous probabilistic
justification: they naturally arise when probability distributions over
different features of proteins need to be combined. We call these quantities
reference ratio distributions deriving from the application of the reference
ratio method. This new view is not only of theoretical relevance, but leads to
many insights that are of direct practical use: the reference state is uniquely
defined and does not require external physical insights; the approach can be
generalized beyond pairwise distances to arbitrary features of protein
structure; and it becomes clear for which purposes the use of these quantities
is justified. We illustrate these insights with two applications, involving the
radius of gyration and hydrogen bonding. In the latter case, we also show how
the reference ratio method can be iteratively applied to sculpt an energy
funnel. Our results considerably increase the understanding and scope of energy
functions derived from known biomolecular structures
Deriving amino acid contact potentials from their frequencies of occurence in proteins: a lattice model study
The possibility of deriving the contact potentials between amino acids from
their frequencies of occurence in proteins is discussed in evolutionary terms.
This approach allows the use of traditional thermodynamics to describe such
frequencies and, consequently, to develop a strategy to include in the
calculations correlations due to the spatial proximity of the amino acids and
to their overall tendency of being conserved in proteins. Making use of a
lattice model to describe protein chains and defining a "true" potential, we
test these strategies by selecting a database of folding model sequences,
deriving the contact potentials from such sequences and comparing them with the
"true" potential. Taking into account correlations allows for a markedly better
prediction of the interaction potentials
The crust in the pamir: Insights from receiver functions
The Cenozoic convergence between India and Asia has created Earth's thickest crust in the Pamir‐Tibet Plateau by extreme crustal shortening. Here we study the crustal structure of the Pamir and western Tian Shan, the adjacent margins of the Tajik, Tarim, and Ferghana Basins, and the Hindu Kush, using data collected by temporary seismic experiments. We derive, compare, and combine independent observations from P and S receiver functions. The obtained Moho depth varies from ~40 km below the basins to a double‐normal thickness of 65–75 km underneath the Pamir and Hindu Kush. A Moho doublet—with the deeper interface down to a depth of ~90 km—coincides with the arc of intermediate‐depth seismicity underneath the Pamir, where Asian continental lower crust delaminates and rolls back. The crust beneath most of the Central and South Pamir has a low Vp/Vs ratio (<1.70), suggesting a dominantly felsic composition, probably a result of delamination/foundering of the mafic rocks of the lower crust. Beneath the Cenozoic gneiss domes of the Central and South Pamir, which represent extensional core complexes, the Vp/Vs ratios are moderate to high (~1.75), consistent with the previously observed, midcrustal low‐velocity zones, implying the presence of crustal partial melts. Even higher crustal average Vp/Vs ratios up to 1.90 are found in the sedimentary basins and along the Main Pamir Thrust. The ratios along the latter—the active thrust front of the Pamir—may reflect fluid accumulations within a strongly fractured fault system
Global Optimization by Energy Landscape Paving
We introduce a novel heuristic global optimization method, energy landscape
paving (ELP), which combines core ideas from energy surface deformation and
tabu search. In appropriate limits, ELP reduces to existing techniques. The
approach is very general and flexible and is illustrated here on two protein
folding problems. For these examples, the technique gives faster convergence to
the global minimum than previous approaches.Comment: to appear in Phys. Rev. Lett. (2002
Partition Function Zeros and Finite Size Scaling of Helix-Coil Transitions in a Polypeptide
We report on multicanonical simulations of the helix-coil transition of a
polypeptide. The nature of this transition was studied by calculating partition
function zeros and the finite-size scaling of various quantities. Estimates for
critical exponents are presented.Comment: RevTex, 4 eps-files; to appear in Phys. Rev. Le
Generalized-ensemble Monte carlo method for systems with rough energy landscape
We present a novel Monte Carlo algorithm which enhances equilibrization of
low-temperature simulations and allows sampling of configurations over a large
range of energies. The method is based on a non-Boltzmann probability weight
factor and is another version of the so-called generalized-ensemble techniques.
The effectiveness of the new approach is demonstrated for the system of a small
peptide, an example of the frustrated system with a rugged energy landscape.Comment: Latex; ps-files include
Analysis of RNA Binding by the Dengue Virus NS5 RNA Capping Enzyme
Flaviviruses are small, capped positive sense RNA viruses that replicate in the cytoplasm of infected cells. Dengue virus and other related flaviviruses have evolved RNA capping enzymes to form the viral RNA cap structure that protects the viral genome and directs efficient viral polyprotein translation. The N-terminal domain of NS5 possesses the methyltransferase and guanylyltransferase activities necessary for forming mature RNA cap structures. The mechanism for flavivirus guanylyltransferase activity is currently unknown, and how the capping enzyme binds its diphosphorylated RNA substrate is important for deciphering how the flavivirus guanylyltransferase functions. In this report we examine how flavivirus NS5 N-terminal capping enzymes bind to the 5′ end of the viral RNA using a fluorescence polarization-based RNA binding assay. We observed that the KD for RNA binding is approximately 200 nM Dengue, Yellow Fever, and West Nile virus capping enzymes. Removal of one or both of the 5′ phosphates reduces binding affinity, indicating that the terminal phosphates contribute significantly to binding. RNA binding affinity is negatively affected by the presence of GTP or ATP and positively affected by S-adensyl methoninine (SAM). Structural superpositioning of the dengue virus capping enzyme with the Vaccinia virus VP39 protein bound to RNA suggests how the flavivirus capping enzyme may bind RNA, and mutagenesis analysis of residues in the putative RNA binding site demonstrate that several basic residues are critical for RNA binding. Several mutants show differential binding to 5′ di-, mono-, and un-phosphorylated RNAs. The mode of RNA binding appears similar to that found with other methyltransferase enzymes, and a discussion of diphosphorylated RNA binding is presented
From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions
©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein
Metropolis simulations of Met-Enkephalin with solvent-accessible area parameterizations
We investigate the solvent-accessible area method by means of Metropolis
simulations of the brain peptide Met-Enkephalin at 300. For the energy
function ECEPP/2 nine atomic solvation parameter (ASP) sets are studied. The
simulations are compared with one another, with simulations with a distance
dependent electrostatic permittivity , and with vacuum
simulations (). Parallel tempering and the biased Metropolis
techniques RM are employed and their performance is evaluated. The measured
observables include energy and dihedral probability densities (pds), integrated
autocorrelation times, and acceptance rates. Two of the ASP sets turn out to be
unsuitable for these simulations. For all other systems selected configurations
are minimized in search of the global energy minima, which are found for the
vacuum and the system, but for none of the ASP models. Other
observables show a remarkable dependence on the ASPs. In particular, we find
three ASP sets for which the autocorrelations at 300K are considerably
smaller than for vacuum simulations.Comment: 10 pages and 8 figure
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