Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cross-crystal averaging with search models to improve molecular replacement phases.

ABSTRACT: The application of molecular replacement (MR) in macromolecular crystallography can be limited by the "model bias" problem. Here we propose a strategy to reduce model bias when only part of a new structure is known: after the MR search, structure determination of the unknown part of the new structure can be facilitated by cross-crystal averaging of the known part of the new structure with the search model. This strategy dramatically improves electron density in the unknown part of the new structure. It has enabled us to determine the structures of two coronavirus receptor-binding domains each complexed with their receptor at moderate resolutions. In a test case, it also enabled automated model building when >50% of an antigen-antibody complex was absent. These results suggest that this averaging strategy can be routinely used after MR to enhance the interpretability of electron density associated with missing model.

SUBMITTER: Li W

PROVIDER: S-EPMC3037595 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Cross-crystal averaging with search models to improve molecular replacement phases.

Li Weikai W Li Fang F

Structure (London, England : 1993) 20110201 2

The application of molecular replacement (MR) in macromolecular crystallography can be limited by the "model bias" problem. Here we propose a strategy to reduce model bias when only part of a new structure is known: after the MR search, structure determination of the unknown part of the new structure can be facilitated by cross-crystal averaging of the known part of the new structure with the search model. This strategy dramatically improves electron density in the unknown part of the new struct ...[more]

PMID: 21300285

Similar Datasets

Local error estimates dramatically improve the utility of homology models for solving crystal structures by molecular replacement.

Project description:Predicted structures submitted for CASP10 have been evaluated as molecular replacement models against the corresponding sets of structure factor amplitudes. It has been found that the log-likelihood gain score computed for each prediction correlates well with common structure quality indicators but is more sensitive when the accuracy of the models is high. In addition, it was observed that using coordinate error estimates submitted by predictors to weight the model can improve its utility in molecular replacement dramatically, and several groups have been identified who reliably provide accurate error estimates that could be used to extend the application of molecular replacement for low-homology cases.

| S-EPMC4321884 | biostudies-literature

MR-REX: molecular replacement by cooperative conformational search and occupancy optimization on low-accuracy protein models.

Project description:Molecular replacement (MR) has commonly been employed to derive the phase information in protein crystal X-ray diffraction, but its success rate decreases rapidly when the search model is dissimilar to the target. MR-REX has been developed to perform an MR search by replica-exchange Monte Carlo simulations, which enables cooperative rotation and translation searches and simultaneous clash and occupancy optimization. MR-REX was tested on a set of 1303 protein structures of different accuracies and successfully placed 699 structures at positions that have an r.m.s.d. of below 2 Å to the target position, which is 10% higher than was obtained by Phaser. However, cases studies show that many of the models for which Phaser failed and MR-REX succeeded can be solved by Phaser by pruning them and using nondefault parameters. The factors effecting success and the parts of the methodology which lead to success are studied. The results demonstrate a new avenue for molecular replacement which outperforms (and has results that are complementary to) the state-of-the-art MR methods, in particular for distantly homologous proteins.

| S-EPMC6038387 | biostudies-literature

Improvement of molecular-replacement models with Sculptor.

Project description:In molecular replacement, the quality of models can be improved by transferring information contained in sequence alignment to the template structure. A family of algorithms has been developed that make use of the sequence-similarity score calculated from residue-substitution scores smoothed over nearby residues to delete or downweight parts of the model that are unreliable. These algorithms have been implemented in the program Sculptor, together with well established methods that are in common use for model improvement. An analysis of the new algorithms has been performed by studying the effect of algorithm parameters on the quality of models. Benchmarking against existing techniques shows that models from Sculptor compare favourably, especially if the alignment is unreliable. Carrying out multiple trials using alternative models created from the same structure but using different algorithm parameters can significantly improve the success rate.

| S-EPMC3069745 | biostudies-literature

The utility of comparative models and the local model quality for protein crystal structure determination by Molecular Replacement.

Project description:BackgroundComputational models of protein structures were proved to be useful as search models in Molecular Replacement (MR), a common method to solve the phase problem faced by macromolecular crystallography. The success of MR depends on the accuracy of a search model. Unfortunately, this parameter remains unknown until the final structure of the target protein is determined. During the last few years, several Model Quality Assessment Programs (MQAPs) that predict the local accuracy of theoretical models have been developed. In this article, we analyze whether the application of MQAPs improves the utility of theoretical models in MR.ResultsFor our dataset of 615 search models, the real local accuracy of a model increases the MR success ratio by 101% compared to corresponding polyalanine templates. On the contrary, when local model quality is not utilized in MR, the computational models solved only 4.5% more MR searches than polyalanine templates. For the same dataset of the 615 models, a workflow combining MR with predicted local accuracy of a model found 45% more correct solution than polyalanine templates. To predict such accuracy MetaMQAPclust, a "clustering MQAP" was used.ConclusionsUsing comparative models only marginally increases the MR success ratio in comparison to polyalanine structures of templates. However, the situation changes dramatically once comparative models are used together with their predicted local accuracy. A new functionality was added to the GeneSilico Fold Prediction Metaserver in order to build models that are more useful for MR searches. Additionally, we have developed a simple method, AmIgoMR (Am I good for MR?), to predict if an MR search with a template-based model for a given template is likely to find the correct solution.

| S-EPMC3534383 | biostudies-literature

Assessing the utility of CASP14 models for molecular replacement.

Project description:The assessment of CASP models for utility in molecular replacement is a measure of their use in a valuable real-world application. In CASP7, the metric for molecular replacement assessment involved full likelihood-based molecular replacement searches; however, this restricted the assessable targets to crystal structures with only one copy of the target in the asymmetric unit, and to those where the search found the correct pose. In CASP10, full molecular replacement searches were replaced by likelihood-based rigid-body refinement of models superimposed on the target using the LGA algorithm, with the metric being the refined log-likelihood-gain (LLG) score. This enabled multi-copy targets and very poor models to be evaluated, but a significant further issue remained: the requirement of diffraction data for assessment. We introduce here the relative-expected-LLG (reLLG), which is independent of diffraction data. This reLLG is also independent of any crystal form, and can be calculated regardless of the source of the target, be it X-ray, NMR or cryo-EM. We calibrate the reLLG against the LLG for targets in CASP14, showing that it is a robust measure of both model and group ranking. Like the LLG, the reLLG shows that accurate coordinate error estimates add substantial value to predicted models. We find that refinement by CASP groups can often convert an inadequate initial model into a successful MR search model. Consistent with findings from others, we show that the AlphaFold2 models are sufficiently good, and reliably so, to surpass other current model generation strategies for attempting molecular replacement phasing.

| S-EPMC8881082 | biostudies-literature

MALMEM: model averaging in linear measurement error models.

Project description:We develop model averaging estimation in the linear regression model where some covariates are subject to measurement error. The absence of the true covariates in this framework makes the calculation of the standard residual-based loss function impossible. We take advantage of the explicit form of the parameter estimators and construct a weight choice criterion. It is asymptotically equivalent to the unknown model average estimator minimizing the loss function. When the true model is not included in the set of candidate models, the method achieves optimality in terms of minimizing the relative loss, whereas, when the true model is included, the method estimates the model parameter with root n rate. Simulation results in comparison with existing Bayesian information criterion and Akaike information criterion model selection and model averaging methods strongly favour our model averaging method. The method is applied to a study on health.

| S-EPMC7450939 | biostudies-literature

Averaging principle for second-order approximation of heterogeneous models with homogeneous models.

Project description:Typically, models with a heterogeneous property are considerably harder to analyze than the corresponding homogeneous models, in which the heterogeneous property is replaced by its average value. In this study we show that any outcome of a heterogeneous model that satisfies the two properties of differentiability and symmetry is O(?(2)) equivalent to the outcome of the corresponding homogeneous model, where ? is the level of heterogeneity. We then use this averaging principle to obtain new results in queuing theory, game theory (auctions), and social networks (marketing).

| S-EPMC3511751 | biostudies-literature

Challenging semi-bootstrapping molecular-replacement strategy reveals intriguing crystal packing of rhizavidin.

Project description:The structure of rhizavidin, the first dimeric member of the avidin family which maintains high affinity towards biotin, was determined to high resolution by SeMet SAD. Consequently, the structure of the rhizavidin-biotin complex was determined by molecular-replacement methods using the apo structure as the search model; this ran into complications and required combined programs as well as bootstrapping approaches. Although present as a dimer in solution, rhizavidin packs as unique oligomers in both crystal forms. The novel insights derived from the unique molecular-replacement procedure and the crystal-driven oligomeric forms in this work may have utililty in biotechological and nanotechnological applications.

| S-EPMC2852325 | biostudies-literature

Crystallographic molecular replacement using an in silico-generated search model of SARS-CoV-2 ORF8.

Project description:The majority of crystal structures are determined by the method of molecular replacement (MR). The range of application of MR is limited mainly by the need for an accurate search model. In most cases, pre-existing experimentally determined structures are used as search models. In favorable cases, ab initio predicted structures have yielded search models adequate for MR. The ORF8 protein of SARS-CoV-2 represents a challenging case for MR using an ab initio prediction because ORF8 has an all β-sheet fold and few orthologs. We previously determined experimentally the structure of ORF8 using the single anomalous dispersion (SAD) phasing method, having been unable to find an MR solution to the crystallographic phase problem. Following a report of an accurate prediction of the ORF8 structure, we assessed whether the predicted model would have succeeded as an MR search model. A phase problem solution was found, and the resulting structure was refined, yielding structural parameters equivalent to the original experimental solution.

| S-EPMC7980513 | biostudies-literature

How far are we from automatic crystal structure solution via molecular-replacement techniques?

Project description:Although the success of molecular-replacement techniques requires the solution of a six-dimensional problem, this is often subdivided into two three-dimensional problems. REMO09 is one of the programs which have adopted this approach. It has been revisited in the light of a new probabilistic approach which is able to directly derive conditional distribution functions without passing through a previous calculation of the joint probability distributions. The conditional distributions take into account various types of prior information: in the rotation step the prior information may concern a non-oriented model molecule alone or together with one or more located model molecules. The formulae thus obtained are used to derive figures of merit for recognizing the correct orientation in the rotation step and the correct location in the translation step. The phases obtained by this new version of REMO09 are used as a starting point for a pipeline which in its first step extends and refines the molecular-replacement phases, and in its second step creates the final electron-density map which is automatically interpreted by CAB, an automatic model-building program for proteins and DNA/RNA structures.

| S-EPMC6939436 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data