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Robotically assisted titration coupled to ion mobility-mass spectrometry reveals the interface structures and analysis parameters critical for multiprotein topology mapping.

ABSTRACT: Multiprotein complexes have three-dimensional shapes and dynamic functions that impact almost every aspect of biochemistry. Despite this, our ability to rapidly assess the structures of such macromolecules lags significantly behind high-throughput efforts to identify their function, especially in the context of human disease. Here, we describe results obtained by coupling ion mobility-mass spectrometry with automated robotic sampling of different solvent compositions. This combination of technologies has allowed us to explore an extensive set of solution conditions for a group of eight protein homotetramers, representing a broad sample of protein structure and stability space. We find that altering solution ionic strength in concert with dimethylsulfoxide content is sufficient to disrupt the protein-protein interfaces of all of the complexes studied here. Ion mobility measurements captured for both intact assemblies and subcomplexes match expected values from available X-ray structures in all cases save two. For these exceptions, we find that distorted subcomplexes result from extreme disruption conditions, and are accompanied by small shifts in intact tetramers size, thus enabling the removal of distorted subcomplex data in downstream models. Furthermore, we find strong correlations between the relative intensities of disrupted protein tetramers and the relative number and type of interactions present at interfaces as a function of disrupting agent added. In most cases, this correlation appears strong enough to quantify various types of protein interfacial interactions within unknown proteins following appropriate calibration.

SUBMITTER: Zhong Y

PROVIDER: S-EPMC3895495 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Robotically assisted titration coupled to ion mobility-mass spectrometry reveals the interface structures and analysis parameters critical for multiprotein topology mapping.

Zhong Yueyang Y Feng Jun J Ruotolo Brandon T BT

Analytical chemistry 20131111 23

Multiprotein complexes have three-dimensional shapes and dynamic functions that impact almost every aspect of biochemistry. Despite this, our ability to rapidly assess the structures of such macromolecules lags significantly behind high-throughput efforts to identify their function, especially in the context of human disease. Here, we describe results obtained by coupling ion mobility-mass spectrometry with automated robotic sampling of different solvent compositions. This combination of technol ...[more]

PMID: 24164205

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Project description:The value of robotically assisted surgery for mitral valve disease is questioned because the high cost of care associated with robotic technology may outweigh its clinical benefits.To investigate conditions under which benefits of robotically assisted surgery mitigate high technology costs.Clinical cohort study at a large multispecialty academic medical center comparing costs of robotically assisted surgery with 3 contemporaneous conventional surgical approaches for degenerative mitral valve disease. From January 1, 2006, through December 31, 2010, a total of 1290 patients with a mean (SD) age of 57 (11) years underwent mitral valve repair for regurgitation from posterior leaflet prolapse. Robotically assisted surgery was performed in 473 patients, complete sternotomy in 227, partial sternotomy in 349, and anterolateral thoracotomy in 241. Comparisons were based on intent to treat, with 3 propensity-matched groups formed based on demographics, symptoms, cardiac and noncardiac comorbidities, valve pathophysiologic disorders, and echocardiographic measurements: robotic vs sternotomy (198 pairs) vs partial sternotomy (293 pairs) vs thoracotomy (224 pairs).Mitral valve repair.Cost of care (expressed as robotic capital investment, maintenance of equipment, and direct technical hospital costs) and benefit of care (based on differences in recovery time).Cost of care (median [15th and 85th percentiles]) for robotically assisted surgery exceeded that of alternative approaches by 26.8% (-5.3% and 67.9%), 32.1% (-6.1% and 69.6%), and 20.7% (-2.4% and 48.4%) for complete sternotomy, partial sternotomy, and anterolateral thoracotomy, respectively. Higher operative costs were partially offset by lower postoperative costs and earlier return to work: a median (15th and 85th percentiles) of 35 (19 and 63) days for robotically assisted surgery, 49 (21 and 109) days for complete sternotomy, 56 (30 and 119) days for partial sternotomy, and 42 (18 and 90) days for anterolateral thoracotomy. Resulting net differences (median [15th and 85th percentiles]) in the cost of robotic surgery vs the 3 alternatives were 15.6% (-14.7% and 55.1%), 15.7% (-19.4% and 51.2%), and 14.8% (-7.4% and 43.6%), respectively. Beyond a volume threshold of 55 to 100 robotically assisted operations per year, distribution of the cost of this technology broadly overlapped those of conventional approaches.In exchange for higher procedural costs, robotically assisted surgery for mitral valve repair offers the clinical benefit of least-invasive surgery, lowest postoperative cost, and fastest return to work. The value of robotically assisted surgery that is similar to that of conventional approaches can be realized only in high-volume centers.

Dataset Information

Robotically assisted titration coupled to ion mobility-mass spectrometry reveals the interface structures and analysis parameters critical for multiprotein topology mapping.

Publications

Robotically assisted titration coupled to ion mobility-mass spectrometry reveals the interface structures and analysis parameters critical for multiprotein topology mapping.

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