Biology subjects

Schwieters, C.

Publications and source records attributed to Schwieters, C..

3 recordsLinked to original sources

bioRxiv2024

Restraint Validation of Biomolecular Structures Determined by NMR in the Protein Data Bank

Biomolecular structure analysis from experimental NMR studies generally relies on restraints derived from a combination of experimental and knowledge-based data. A challenge for the structural biology community has been a lack of standards for representing these restraints, preventing the establishment of uniform methods of model-vs-data structure validation against restraints and limiting interoperability between restraint-based structure modeling programs. The NMR exchange (NEF) and NMR-STAR formats provide a standardized approach for representing commonly used NMR restraints. Using these restraint formats, a standardized validation system for assessing structural models of biopolymers against restraints has been developed and implemented in the wwPDB OneDep data deposition-validation-biocuration system. The resulting wwPDB Restraint Violation Report provides a model vs. data assessment of biomolecule structures determined using distance and dihedral restraints, with extensions to other restraint types currently being implemented. These tools are useful for assessing NMR models, as well as for assessing biomolecular structure predictions based on distance restraints. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/575520v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@bac5eforg.highwire.dtl.DTLVardef@190cdborg.highwire.dtl.DTLVardef@9b3d83org.highwire.dtl.DTLVardef@1e38ccc_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPDB Structure Validation Report expanded to include Restraint Analysis C_LIO_LINMR Exchange Format (NEF) and NMR-STAR for distance restraint representation C_LIO_LIStandard distance and dihedral restraint formats for model vs. restraint assessment C_LIO_LIStandardized restraint formats provide interoperability between modeling programs C_LI

bioinformatics↗

bioRxiv2018

Integrated NMR and cryo-EM atomic-resolution structure determination of a half-megadalton enzyme complex

Atomic-resolution structure determination is the key requirement for understanding protein function. Cryo-EM and NMR spectroscopy both provide structural information, but currently cryo-EM does not routinely give access to atomic-level structural data, and, generally, NMR structure determination is restricted to small (<30 kDa) proteins. We introduce an integrated structure determination approach that simultaneously uses NMR and EM data to overcome the limits of each of these methods. The approach enabled determination of the high-resolution structure of the 468 kDa large dodecameric aminopeptidase TET2 to a precision and accuracy below 1 [A] by combining secondary-structure information obtained from near-complete magic-angle-spinning NMR assignments of the 39 kDa-large subunits, distance restraints from backbone amides and specifically labelled methyl groups, and a 4.1 [A] resolution EM map. The resulting structure exceeds current standards of NMR and EM structure determination in terms of molecular weight and precision. Importantly, the approach is successful even in cases where only medium-resolution (up to 8 [A]) cryo-EM data are available, thus paving avenues for the structure determination of challenging biological assemblies.

biophysics↗

bioRxiv2018

Robust nomenclature and software for enhanced reproducibility in molecular modeling of small molecules

Computational molecular dynamics, energy minimization, and modeling of molecular interactions are widely used in studies involving natural products, metabolites, and drugs. Manually directed computational steps commonly utilize an evolving collection of experimental and computational data, to which new data sources are added or modified as needed. Several software packages capable of incorporating sources of data are available, but the process remains error prone owing to the complexities of preparing and maintaining a consistent set of input files and the proper post-processing of derived data. We have devised a methodology and implemented it using an extensible software pipeline called RUNER (for Robust and Unique Nomenclature for Enhanced Reproducibility) that creates a robust and standardized computational process. The pipeline combines a web service and a graphical user interface (GUI) to enable seamless modifications and verified maintenance of atom force field parameters. The GUI provides an implementation for the widely used molecular modeling software package Xplor-NIH. We describe the RUNER software and demonstrate the rationale for the pipeline through examples of structural studies of small molecules and natural products. The software, pipeline, force field parameters, and file verification data for more than 4,100 compounds (including FDA-approved drugs and natural products) are freely accessible from [http://runer.nmrfam.wisc.edu].\n\nAuthor SummaryWe describe an automated and verifiable computational pipeline for calculating the force field parameters of small molecules. The pipeline integrates several software tools and guarantees reproducibility of the parameters by utilizing a standard nomenclature across multiple computational steps and by maintaining file verification identifiers. We demonstrate the application of this pipeline to (a) processing of more than 4,100 compounds in high-throughput mode, and (b) structural studies of natural products. The graphical user interface (GUI) associated with the pipeline facilitates the manually tedious steps of force field parameters adjustments and supports visualization of the process.

bioinformatics↗