Native Mass Spectrometry Resources

Native mass spectrometry (native MS) enables protein structural analysis by preserving the native structure and non-covalent interactions of proteins, protein complexes, and protein–ligand assemblies during mass spectrometry analyses. This allows researchers to characterize intact biomolecules under near-physiological conditions and obtain structural information that is difficult to access with denaturing methods.

Native MS can provide:

• Accurate molecular mass measurements of intact proteins and complexes.
• Protein complex stoichiometry, revealing the number and arrangement of subunits.
• Protein–protein and protein–ligand interaction analysis, including binding specificity and affinity.
• Structural heterogeneity assessment, including proteoforms and post-translational modifications (PTMs) such as glycosylation.
• Sample quality and homogeneity screening before structural biology techniques such as cryo-electron microscopy (cryo-EM).
• Label-free ligand screening for rapid identification of binding events in drug discovery.
• Characterization of large and heterogeneous biomolecular assemblies when combined with advanced approaches such as charge detection mass spectrometry (CDMS) and top-down mass spectrometry.

Because native MS delivers rapid, high-resolution, and biologically relevant structural information, it is widely used in structural biology, biopharmaceutical development, and protein interaction research.

Orbitrap-based mass spectrometers provide significant advantages for native mass spectrometry (native MS) because they combine high-resolution accurate-mass (HRAM) measurements, high sensitivity, and extended mass range with workflows designed to preserve non-covalent interactions. These capabilities enable confident characterization of intact proteins, protein complexes, and other large biomolecular assemblies under near-native conditions.

Key advantages of Orbitrap-based mass spectrometers for  native MS include:

• High-resolution accurate-mass (HRAM) analysis for precise measurement of intact proteins and macromolecular complexes.
• Accurate determination of stoichiometry and molecular composition, including heterogeneous protein assemblies.
• Extended high m/z performance for analyzing large biomolecules, viruses, membrane proteins, and protein complexes.
• Charge detection mass spectrometry (CDMS) capabilities on selected platforms for direct mass measurement of highly heterogeneous and ultra-high-mass analytes.
• Advanced top-down fragmentation to characterize intact proteins, localize post-translational modifications (PTMs), and improve sequence coverage.
• Flexible workflows that support native protein characterization, ligand binding studies, online buffer exchange, and cryo-EM sample screening.
• Integrated software for deconvolution, complex composition analysis, stoichiometry determination, and proteoform characterization.

Together, these capabilities make Orbitrap-based mass spectrometers powerful platforms for structural biology, biopharmaceutical characterization, and native protein analysis, delivering comprehensive insights into molecular mass, higher-order structure, protein interactions, and biomolecular heterogeneity.

Native mass spectrometry (native MS) complements cryo-electron microscopy (cryo-EM) by providing rapid, high-resolution characterization of proteins and protein complexes before high-resolution structure determination. Native MS preserves non-covalent interactions, enabling researchers to confirm molecular mass, subunit stoichiometry, ligand binding, sample homogeneity, and post-translational modifications (PTMs) under near-native conditions. By screening samples prior to cryo-EM, native MS helps identify intact, homogeneous protein complexes, reducing time spent on unsuitable samples and increasing confidence in structural biology workflows. Together, native MS and cryo-EM provide complementary insights into protein composition, interactions, and three-dimensional structure for structural biology and biopharmaceutical research.

Native mass spectrometry (native MS) reveals key structural and functional properties of proteins while preserving their native conformation and non-covalent interactions. By analyzing intact proteins and protein complexes under near-physiological conditions, native MS provides insights that complement other structural biology techniques.

Native MS can reveal:

• Molecular mass of intact proteins and macromolecular complexes.
• Protein complex stoichiometry and subunit composition.
• Protein–protein and protein–ligand interactions, including complex formation and binding specificity.
• Structural heterogeneity, including different proteoforms and post-translational modifications (PTMs) such as glycosylation.
• Sample homogeneity and stability to assess suitability for downstream structural studies.
• Higher-order structural organization by preserving biologically relevant assemblies in the gas phase.

These capabilities make native mass spectrometry an essential tool for structural biology, biopharmaceutical characterization, and drug discovery, while complementing high-resolution techniques such as cryo-electron microscopy (cryo-EM).