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Using singular value decomposition to characterize protein-protein interactions by in-cell NMR spectroscopy.

ABSTRACT: Distinct differences between how model proteins interact in-cell and in vitro suggest that the cytosol might have a profound effect in modulating protein-protein and/or protein-ligand interactions that are not observed in vitro. Analyses of in-cell NMR spectra of target proteins interacting with physiological partners are further complicated by low signal-to-noise ratios, and the long overexpression times used in protein-protein interaction studies may lead to changes in the in-cell spectra over the course of the experiment. To unambiguously resolve the principal binding mode between two interacting species against the dynamic cellular background, we analyzed in-cell spectral data of a target protein over the time course of overexpression of its interacting partner by using single-value decomposition (SVD). SVD differentiates between concentration-dependent and concentration-independent events and identifies the principal binding mode between the two species. The analysis implicates a set of amino acids involved in the specific interaction that differs from previous NMR analyses but is in good agreement with crystallographic data.

SUBMITTER: Majumder S

PROVIDER: S-EPMC4041589 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Using singular value decomposition to characterize protein-protein interactions by in-cell NMR spectroscopy.

Majumder Subhabrata S DeMott Christopher M CM Burz David S DS Shekhtman Alexander A

Chembiochem : a European journal of chemical biology 20140401 7

Distinct differences between how model proteins interact in-cell and in vitro suggest that the cytosol might have a profound effect in modulating protein-protein and/or protein-ligand interactions that are not observed in vitro. Analyses of in-cell NMR spectra of target proteins interacting with physiological partners are further complicated by low signal-to-noise ratios, and the long overexpression times used in protein-protein interaction studies may lead to changes in the in-cell spectra over ...[more]

PMID: 24692227

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Project description:BackgroundBoth microarrays and quantitative real-time PCR are convenient tools for studying the transcriptional levels of genes. The former is preferable for large scale studies while the latter is a more targeted technique. Because of platform-dependent systematic effects, simple comparisons or merging of datasets obtained by these technologies are difficult, even though they may often be desirable. These difficulties are exacerbated if there is only partial overlap between the experimental conditions and genes probed in the two datasets.ResultsWe show here that the generalized singular value decomposition provides a practical tool for merging a small, targeted dataset obtained by quantitative real-time PCR of specific genes with a much larger microarray dataset. The technique permits, for the first time, the identification of genes present in only one dataset co-expressed with a target gene present exclusively in the other dataset, even when experimental conditions for the two datasets are not identical. With the rapidly increasing number of publically available large scale microarray datasets the latter is frequently the case. The method enables us to discover putative candidate genes involved in the biosynthesis of the (1,3;1,4)-beta-D-glucan polysaccharide found in plant cell walls.ConclusionWe show that the generalized singular value decomposition provides a viable tool for a combined analysis of two gene expression datasets with only partial overlap of both gene sets and experimental conditions. We illustrate how the decomposition can be optimized self-consistently by using a judicious choice of genes to define it. The ability of the technique to seamlessly define a concept of "co-expression" across both datasets provides an avenue for meaningful data integration. We believe that it will prove to be particularly useful for exploiting large, publicly available, microarray datasets for species with unsequenced genomes by complementing them with more limited in-house expression measurements.

Project description:BackgroundFor marker effect models and genomic animal models, computational requirements increase with the number of loci and the number of genotyped individuals, respectively. In the latter case, the inverse genomic relationship matrix (GRM) is typically needed, which is computationally demanding to compute for large datasets. Thus, there is a great need for dimensionality-reduction methods that can analyze massive genomic data. For this purpose, we developed reduced-dimension singular value decomposition (SVD) based models for genomic prediction.MethodsFast SVD is performed by analyzing different chromosomes/genome segments in parallel and/or by restricting SVD to a limited core of genotyped individuals, producing chromosome- or segment-specific principal components (PC). Given a limited effective population size, nearly all the genetic variation can be effectively captured by a limited number of PC. Genomic prediction can then be performed either by PC ridge regression (PCRR) or by genomic animal models using an inverse GRM computed from the chosen PC (PCIG). In the latter case, computation of the inverse GRM will be feasible for any number of genotyped individuals and can be readily produced row- or element-wise.ResultsUsing simulated data, we show that PCRR and PCIG models, using chromosome-wise SVD of a core sample of individuals, are appropriate for genomic prediction in a larger population, and results in virtually identical predicted breeding values as the original full-dimension genomic model (r = 1.000). Compared with other algorithms (e.g. algorithm for proven and young animals, APY), the (chromosome-wise SVD-based) PCRR and PCIG models were more robust to size of the core sample, giving nearly identical results even down to 500 core individuals. The method was also successfully tested on a large multi-breed dataset.ConclusionsSVD can be used for dimensionality reduction of large genomic datasets. After SVD, genomic prediction using dense genomic data and many genotyped individuals can be done in a computationally efficient manner. Using this method, the resulting genomic estimated breeding values were virtually identical to those computed from a full-dimension genomic model.

Project description:Photoacoustic imaging (PAI) can be used to infer molecular information about myocardial health non-invasively in vivo using optical excitation at ultrasonic spatial resolution. For clinical and preclinical linear array imaging systems, conventional delay-and-sum (DAS) beamforming is typically used. However, DAS cardiac PA images are prone to artifacts such as diffuse quasi-static clutter with temporally varying noise-reducing myocardial signal specificity. Typically, multiple frame averaging schemes are utilized to improve the quality of cardiac PAI, which affects the spatial and temporal resolution and reduces sensitivity to subtle PA signal variation. Furthermore, frame averaging might corrupt myocardial oxygen saturation quantification due to the presence of natural cardiac wall motion. In this paper, a spatiotemporal singular value decomposition (SVD) processing algorithm is proposed to reduce DAS PAI artifacts and subsequent enhancement of myocardial signal specificity. Demonstrate enhancement of PA signals from myocardial tissue compared to surrounding tissues and blood inside the left-ventricular (LV) chamber using spatiotemporal SVD processing with electrocardiogram (ECG) and respiratory signal (ECG-R) gated in vivo murine cardiac PAI. In vivo murine cardiac PAI was performed by collecting single wavelength (850 nm) photoacoustic channel data on eight healthy mice. A three-dimensional (3D) volume of complex PAI data over a cardiac cycle was reconstructed using a custom ECG-R gating algorithm and DAS beamforming. Spatiotemporal SVD was applied on a two-dimensional Casorati matrix generated using the 3D volume of PAI data. The singular value spectrum (SVS) was then filtered to remove contributions from diffuse quasi-static clutter and random noise. Finally, SVD processed beamformed images were derived using filtered SVS and inverse SVD computations. Qualitative comparison with DAS and minimum variance (MV) beamforming shows that SVD processed images had better myocardial signal specificity, contrast, and target detectability. DAS, MV, and SVD images were quantitatively evaluated by calculating contrast ratio (CR), generalized contrast-to-noise ratio (gCNR), and signal-to-noise ratio (SNR). Quantitative evaluations were done at three cardiac time points (during systole, at end-systole (ES), and during diastole) identified from co-registered ultrasound M-Mode image. Mean CR, gCNR, and SNR values of SVD images at ES were 245, 115.15, and 258.17 times higher than DAS images with statistical significance evaluated with one-way analysis of variance. Our results suggest that significantly better-quality images can be realized using spatiotemporal SVD processing for in vivo murine cardiac PAI.

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Using singular value decomposition to characterize protein-protein interactions by in-cell NMR spectroscopy.

Publications

Using singular value decomposition to characterize protein-protein interactions by in-cell NMR spectroscopy.

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