Biomolecular NMR data analysis (original) (raw)

Biomolecular NMR: Past and future

Archives of biochemistry and biophysics, 2017

The editors of this special volume suggested this topic, presumably because of the perspective lent by our combined >90-year association with biomolecular NMR. What follows is our personal experience with the evolution of the field, which we hope will illustrate the trajectory of change over the years. As for the future, one can confidently predict that it will involve unexpected advances. Our narrative is colored by our experience in using the NMR Facility for Biomedical Studies at Carnegie-Mellon University (Pittsburgh) and in developing similar facilities at Purdue (1977-1984) and the University of Wisconsin-Madison (1984-). We have enjoyed developing NMR technology and making it available to collaborators and users of these facilities. Our group's association with the Biological Magnetic Resonance data Bank (BMRB) and with the Worldwide Protein Data Bank (wwPDB) has also been rewarding. Of course, many groups contributed to the early growth and development of biomolecular...

Integrative NMR for biomolecular research

Journal of biomolecular NMR, 2016

NMR spectroscopy is a powerful technique for determining structural and functional features of biomolecules in physiological solution as well as for observing their intermolecular interactions in real-time. However, complex steps associated with its practice have made the approach daunting for non-specialists. We introduce an NMR platform that makes biomolecular NMR spectroscopy much more accessible by integrating tools, databases, web services, and video tutorials that can be launched by simple installation of NMRFAM software packages or using a cross-platform virtual machine that can be run on any standard laptop or desktop computer. The software package can be downloaded freely from the NMRFAM software download page ( http://pine.nmrfam.wisc.edu/download\_packages.html ), and detailed instructions are available from the Integrative NMR Video Tutorial page ( http://pine.nmrfam.wisc.edu/integrative.html ).

An NMR Approach Applicable to Biomolecular Structure Characterization

Analytical Chemistry, 2005

A generalized 2D correlation NMR (GEN2D-NMR) scheme capable of substantially reducing the experimental time for two-dimensional correlation NMR experiments is described. The experimental time used in GEN2D-NMR is shortened to less than one-tenth of that required in traditional double Fourier transform 2D-NMR (FT2D-NMR) for a 13 C-13 C spin diffusion experiment for Nephila edulis spider threads. Experimentally, one needs to acquire many fewer points in GEN2D-NMR than that in FT2D-NMR in the evolution time domain. By keeping other acquisition pulse sequence and parameters the same in both methods, the GEN2D-NMR technique can produce a 2D-NMR spectrum using fewer points along the evolution time domain equivalent to that produced by the FT2D-NMR technique using more points. GEN2D-NMR would provide a significant advantage for those molecules that are difficult to highly isotropically label, such as proteins, polypeptides, and polymers, or those which become unstable in a prolonged measurement time.

Biomolecular NMR: a chaperone to drug discovery

Current Opinion in Chemical Biology, 2006

Biomolecular NMR now contributes routinely to every step in the development of new chemical entities ahead of clinical trials. The versatility of NMR -from detection of ligand binding over a wide range of affinities and a wide range of drug targets with its wealth of molecular information, to metabolomic profiling, both ex vivo and in vivo -has paved the way for broadly distributed applications in academia and the pharmaceutical industry. Proteomics and initial target selection both benefit from NMR: screenings by NMR identify lead compounds capable of inhibiting protein-protein interactions, still one of the most difficult development tasks in drug discovery. NMR hardware improvements have given access to the microgram domain of phytochemistry, which should lead to the discovery of novel bioactive natural compounds. Steering medicinal chemists through the lead optimisation process by providing detailed information about protein-ligand interactions has led to impressive success in the development of novel drugs. The study of biofluid compositionmetabonomics -provides information about pharmacokinetics and helps toxicological safety assessment in animal model systems. In vivo, magnetic resonance spectroscopy interrogates metabolite distributions in living cells and tissues with increasing precision, which significantly impacts the development of anticancer or neurological disorder therapeutics. An overview of different steps in recent drug discovery is presented to illuminate the links with the most recent advances in NMR methodology.

Traditional Biomolecular Structure Determination by NMR Spectroscopy Allows for Major Errors

PLoS Computational Biology, 2005

One of the major goals of structural genomics projects is to determine the three-dimensional structure of representative members of as many different fold families as possible. Comparative modeling is expected to fill the remaining gaps by providing structural models of homologs of the experimentally determined proteins. However, for such an approach to be successful it is essential that the quality of the experimentally determined structures is adequate. In an attempt to build a homology model for the protein dynein light chain 2A (DLC2A) we found two potential templates, both experimentally determined nuclear magnetic resonance (NMR) structures originating from structural genomics efforts. Despite their high sequence identity (96%), the folds of the two structures are markedly different. This urged us to perform in-depth analyses of both structure ensembles and the deposited experimental data, the results of which clearly identify one of the two models as largely incorrect. Next, we analyzed the quality of a large set of recent NMR-derived structure ensembles originating from both structural genomics projects and individual structure determination groups. Unfortunately, a visual inspection of structures exhibiting lower quality scores than DLC2A reveals that the seriously flawed DLC2A structure is not an isolated incident. Overall, our results illustrate that the quality of NMR structures cannot be reliably evaluated using only traditional experimental input data and overall quality indicators as a reference and clearly demonstrate the urgent need for a tight integration of more sophisticated structure validation tools in NMR structure determination projects. In contrast to common methodologies where structures are typically evaluated as a whole, such tools should preferentially operate on a per-residue basis.

Modern NMR spectroscopy of proteins and peptides in solution and its relevance to drug design

The knowledge of the three-dimensional (3D) structures and conformational dynamics of proteins and peptides is important for the understanding of biochemical and genetic data derived for these molecules. This understanding can ultimately be of help in drug design. We describe here the role of Nuclear Magnetic Resonance (NMR) spectroscopy in this process for three distinct situations: for small proteins, where relatively simple NMR methods can be used for fhll 3D structure determination; for larger proteins that require multinuclear multidimensional NMR but for which full 3D structures can still be obtained; and for small peptides that are studied in interaction with macromolecules (receptors) using specialized NMR techniques. A fourth situation, pertaining to large systems where only partial structural information can be obtained from NMR data, is briefly discussed. Molecules of interest to the biomedical field (C5a and stromelysin) are discussed as examples.

NMR as a Progressive Tool for Bimolecular Studies: A Mini Review

Metabolomics is well recognized technique for the analysis of biological system. Recently NMR is becoming an important tool of interest for researchers in the area of bimolecular analysis, especially for drug discovery. This technique is a significant step forward for identifying biomarkers, ligand interaction to the target, pathway recognition and metabolomic mapping. NMR based metabolomic is not only being used for the identification and structure elucidation of synthetic or natural compounds but also is considered as an imperative tool for biomolecular drug discovery. Significant advancements in methodological developments, software (including bioinformatics tools), and hardware (including instrumentation) is exploring new areas for industrial drug discov ery. In this review, we discussed the importance of NMR technique in bio - molecular sciences.