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John A. McLean

Title and Contact Information

Stevenson Professor of Chemistry
Office: 5421 SC
Phone: (615) 322-1195


Ph.D., The George Washington University, 2001


Physical Chemistry
Mass spectrometry
Chemical Biology
Biophysical Chemistry
Bioanalytical Chemistry
Analytical Chemistry

In the News

Journal-Molecular BioSystems
Research News @ Vanderbilt-New technique maps twin faces of smallest Janus nanoparticles
C&E NEWS-"Dr. Michal Kliman (McLean group) featured on the cover of October 10th issue of C&ENews for mass spectrometry and lipidomics"
Arts and Science-John McLean was awarded Excellence in Teaching
Arts and Science-That Alcohol Is Going On Your Permanent Record
Arts and Science-And the Award Goes to
Arts and Science Fall 2008-And the Award Goes to
Research News @ Vanderbilt-Vanderbilt-led team to develop 'microbrain' to improve drug testing
The Tennessean-David Cliffel, John McLean, and colleagues have big hopes on a tiny device
Research News @ Vanderbilt-New tool for mining bacterial genome for novel drugs
Research News @ Vanderbilt-Vanderbilt awarded $16.5 million agreement to determine how toxic agents affect human cells
Research News @ Vanderbilt-'Thought Leader' named for ion mobility mass spectrometry research



Bioanalytical and Biophysical Chemistry
Our research focuses on the design, construction, and application of advanced technologies for structural mass spectrometry, in particular, for studies in structural proteomics, systems biology, and biophysics. To identify and structurally characterize biomolecules from complex samples, we perform rapid (µs-ms) two-dimensional gas-phase separations using ion mobility-mass spectrometry (IM-MS) techniques. IM-MS provides separations on the basis of apparent surface area (ion-neutral collision cross section) and mass-to-charge (m/z), respectively. Biomolecular structural information is interpreted by comparing experimentally obtained collision cross-sections in the context of those obtained via molecular dynamics simulations.

Figure 1. (A) An illustration of the conformation space separation of different classes of biomolecules. Note that the indicated trends in the correlation function of collision cross section and m/z for particular molecular classes are for qualitative illustration purposes. Structural motifs (secondary structural elements, intramolecular solvation of post-translational modifications, etc.) give rise to deviation from the average correlation function within a particular molecular class.

In the analysis of complex biological materials, IM-MS provides a significant advantage over contemporary MS in that the regions in which signals appear in 2D conformation-space correspond with specific molecular class, i.e. the correlation of collision cross section with m/z varies as nucleotides/carbohydrates < peptides/ proteins < lipids/surfactants (Figure 1). Deviations from where a particular signal is predicted to occur can provide additional information including: (i) identification of sights of post-translational modification, (ii) characterization of secondary, tertiary, and quaternary structural motifs, and (iii) rapid screening for analyte-ligand binding interactions. The separation of analytes on the basis of molecular class provides significant advantages as a proteomics tool, because signals arising from concomitant, non-peptidic, materials are readily separated from the peptides of interest. For example, Figure 2 shows a representative IM-MS plot of conformation-space for an HPLC fraction of an E. Coli whole-cell lysate. Signals arising from surfactant contaminant in the sample preparation are resolved from peptides on the basis of structure and can thus be eliminated when searching peptide m/z signals against proteomic and genomic databases for high-confidence level protein identification.

Figure 2. A 3D plot of IM-MS conformation space for a representative E. Coli whole-cell lysate fraction measured by HPLC-MALDI-IM-TOFMS. Two distinct trends of correlated arrival time distribution (which is the observable measured and subsequently transformed to collision-cross section) vs. m/z are obtained corresponding to non-peptidic concomitant species and tryptic peptides, respectively.

Importantly, IM-MS can provide detailed structural information for conformational sub-populations of the same analyte (Figure 3), i.e. the relative abundances of different biomolecular conformations can be readily determined. By measuring the change in relative abundance of specific structural conformations as a function of IM separation temperature, thermodynamic and kinetic parameters can also be determined for structural sub-populations, or for structural transitions, respectively (i.e. via van't Hoff or Arrhenius plots). Note that this procedure can also be used to quantify the thermodynamic consequences of stepwise addition of solvent, or small molecules, on the prevailing molecular structure.

Figure 3. Experimental IM-MS conformation-space for a model peptide exhibiting two distinct structural sub-populations. Structures obtained by molecular dynamics simulations indicate helical and compact structures consistent with these results.

     Key areas of investigation and development include:
  • Investigation of the prevailing influences of post-translational modifications (e.g. glycosylation, phosphorylation, ubiquination, sumoylation, etc.) on protein secondary and tertiary structure?
  • Development of imaging IM-MS instrumentation for multidimensional imaging/characterization of biomarker species from thin tissue sections and microarrays.
  • Combining microfluidic separation strategies with IM-MS for fundamental biomolecular characterization in systems biology.
  • Development of selective IM-MS shift reagents for high confidence level identification in proteomics, glycomics, lipidomics, and metabolomics.
    Development of molecular dynamics strategies for structural interpretation of complementary IM-MS collision cross sections.
  • Construction of advanced laser optical strategies for high-throughput screening of drug-ligand interactions.

Selected Publications

Lamberson, C. R., Xu, L., Muchalski, H., Montenegro-Burke, J. R., Shmanai, V. V., Bekish, A. V., McLean, J. A., Clarke, C. F., Shchepinov, M. S., Porter, N. A. Unusual kinetic isotope effects of deuterium reinforced polyunsaturated fatty acids in tocopherol-mediated free radical chain oxidations. Journal of the American Chemical Society. 2014, 136 (3): 838-41.

May, J. C., Goodwin, C. R., Lareau, N. M., Leaptrot, K. L., Morris, C. B., Kurulugama, R. T., Mordehai, A., Klein, C., Barry, W., Darland, E., Overney, G., Imatani, K., Stafford, G. C., Fjeldsted, J. C., McLean, J. A. Conformational ordering of biomolecules in the gas phase: nitrogen collision cross sections measured on a prototype high resolution drift tube ion mobility-mass spectrometer. Analytical Chemistry. 2014, 86 (4): 2107-16.

Hines, K. M., Ashfaq, S., Davidson, J. M., Opalenik, S. R., Wikswo, J. P., McLean, J. A. Biomolecular Signatures of Diabetic Wound Healing by Structural Mass Spectrometry. Analytical Chemistry. 2013, 85 (7): 3651-3659.

Derewacz, D. K., Goodwin, C. R., McNees, C. R., McLean, J. A., Bachmann, B. O. Antimicrobial drug resistance affects broad changes in metabolomic phenotype in addition to secondary metabolism. Proceedings of The National Academy of Sciences of The United States of America. 2013, 110 (6): 2336-2341.

Harkness, K. M., Tang, Y., Dass, A., Pan, J., Kothalawala, N., Reddy, V. J., Cliffel, D. E., Demeler, B., Stellacci, F., Bakr, O. M., McLean, J. A. Ag-44(SR)(30)(4-): a silver-thiolate superatom complex. Nanoscale. 2012, 4 (14): 4269-4274.

Matusch, A., Fenn, L. S., Depboylu, C., Klietz, M., Strohmer, S., McLean, J. A., Becker, J. S. Combined Elemental and Biomolecular Mass Spectrometry Imaging for Probing the Inventory of Tissue at a Micrometer Scale. Analytical Chemistry. 2012, 84 (7): 3170-3178.

Harkness, K. M., Turner, B. N., Agrawal, A. C., Zhang, Y. B., McLean, J. A., Cliffel, D. E. Biomimetic monolayer-protected gold nanoparticles for immunorecognition. Nanoscale. 2012, 4 (13): 3843-3851.

Goodwin, C. R., Fenn, L. S., Derewacz, D. K., Bachmann, B. O., McLean, J. A. Structural Mass Spectrometry: Rapid Methods for Separation and Analysis of Peptide Natural Products. Journal of Natural Products. 2012, 75 (1): 48-53.

Harkness, K. M., Balinski, B., Mclean, J. A., Cliffel, D. E. Nanoscale Phase Segregation of Mixed Thiolates on Gold Nanoparticles. Angewandte Chemie-International Edition. 2011, 50 (45): 10554-10559.

Kerr, T. J., Gant-Branum, R. L., Mclean, J. A. Multiplexed analysis of peptide functionality using lanthanide-based structural shift reagents. International Journal of Mass Spectrometry. 2011, 307 (1-3): 28-32.

Kliman, M., May, J. C., Mclean, J. A. Lipid analysis and lipidomics by structurally selective ion mobility-mass spectrometry. Biochimica ET Biophysica ACTA-Molecular And Cell Biology Of Lipids. 2011, 1811 (11): 935-945.

Lareau, N. M., Fenn, L. S.,Goodwin, C. R., Bachmann, B. O., Mclean, J. A. Exploring conformation space for natural product discovery. Abstracts of Papers of The American Chemical Society. 2011, 241 (0): 165-CHED.

Fenn, L. S., Mclean, J. A. Structural resolution of carbohydrate positional and structural isomers based on gas-phase ion mobility-mass spectrometry. Physical Chemistry Chemical Physics. 2011, 13 (6): 2196-205.

Fenn, L. S., Mclean, J. A. Structural Characterization of Carbohydrates and Glycoproteins using Ion Mobility-Mass Spectrometry. Glycobiology. 2010, 20 (11): 1474-1474.

Kerr, T. J., McLean, J. A. Peptide quantitation using primary amine selective metal chelation labels for mass spectrometry. Chemical Communications. 2010, 46 (30): 5479-5481.

Ridenour, W.B., Kliman, M., McLean, J.A., Caprioli, R.M. Structural Characterization of Phospholipids and Peptides Directly from Tissue Sections by MALDI Traveling-Wave Ion Mobility-Mass Spectrometry. Analytical Chemistry. 2010, 82 (5): 1881-1889.

Gant-Branum, R.L., Broussard, J.A., Mahsut, A., Webb, D.J., McLean, J.A. Identification of Phosphorylation Sites within the Signaling Adaptor APPL1 by Mass Spectrometry. Journal of Proteome Research. 2010, 9 (3): 1541-1548.

Harkness, K.M., Fenn, L.S., Cliffel, D.E., McLean, J.A. Surface Fragmentation of Complexes from Thiolate Protected Gold Nanoparticles by Ion Mobility-Mass Spectrometry. Analytical Chemistry. 2010, 82 (7): 3061-3066.

Sundarapandian, S., May, J.C., McLean, J.A. Dual Source Ion Mobility-Mass Spectrometer for Direct Comparison of Electrospray Ionization and MALDI Collision Cross Section Measurements. Analytical Chemistry. 2010, 82 (8): 3247-3254.