SLAS Discovery - Special Issue on Advances in MALDI Mass Spectrometry for Drug Discovery - Volume 22 Issue 10 - December 2017 - 1179

735067
research-article2017

JBXXXX10.1177/2472555217735067SLAS DISCOVERY: Advancing Life Sciences R&DCornett and Scholle

Editorial

Advances in MALDI Mass Spectrometry
within Drug Discovery

SLAS Discovery
2017, Vol. 22(10) 1179-1181
© 2017 Society for Laboratory
Automation and Screening
https://doi.org/10.1177/2472555217735067
DOI: 10.1177/2472555217735067
journals.sagepub.com/home/jbx

Dale S. Cornett1 and Michael D. Scholle2
This special issue of SLAS Discovery is dedicated to MALDI
TOF (matrix-assisted laser desorption/ionization time of
flight), marking the 30th anniversary of this revolutionary soft
ionization technique for analyzing nonvolatile biomolecules
using mass spectrometry (MS).1 The technique was termed
MALDI TOF by Hillenkamp and colleagues2 when describing
their process of irradiating co-crystals of analyte and a matrix
compound, usually a small organic acid, with a pulsed laser to
desorb and ionize intact analyte molecules. In this approach,
matrix-analyte mixtures are typically applied onto a metal
MALDI TOF substrate plate in formats that are often amenable to standard laboratory liquid handling. The laser-absorbing
matrix creates ions of the analyte in which its mass is determined by the time of flight to a detector. By combining the
above, MALDI can be applied to the analysis of several types
of biomolecules, including DNA, RNA, peptides, lipids, sugars, and proteins. From an experimental perspective, MALDI
exhibits attractive characteristics that include tolerance to low
concentrations of salts and detergents, straightforward sample
preparation without the need for solid phase extraction, low
fragmentation of the analyte, and the predominant formation
of singly charge ions. This unique combination of properties
has allowed MALDI to become an invaluable tool for analyzing many classes of nonvolatile compounds.
Matrix is a critical component of MALDI TOF MS that
assists in the ionization of analytes. Compounds that make
an effective matrix are more often discovered rather than
chosen. Although the general properties of an effective
matrix have been used to design an enhanced matrix compound,3 possession of these ionization mechanisms does not
necessarily guarantee a compound to be an effective matrix
for all analytes. There are only three commonly used matrix
compounds: α-cyano-4-hydroxycinnamic acid (α-CHCA or
alpha-cyano); 3,5-dimethoxy-4-hydroxycinnamic acid
(sinapinic acid); and 2,5-dihydroxybenzoic acid (DHB).
Although dozens of other matrix compounds exist, a survey
of these molecules would allow for determining the best
outcome in an experiment (i.e., signal, lack of interference,
ion polarity, etc.).
Common matrix compounds range in size from 200 to
400 Daltons, allowing for easy vaporization by a laser.
Furthermore, the application of matrix molecules in MALDI
can contribute to a strong chemical background of ions
lower than 700-800 m/z from a variety of clustered matrix
molecules. When analyzing biomolecules that are higher

than 1000 m/z, the matrix background does not present significant interference with the intended analyte. When analyte molecules occupy the same m/z space as the interfering
matrix clusters, however, it can be a challenge to differentiate analyte ions from background. Not only is the selection
of matrix a key component of MALDI, but also the solvents
and additives used and how matrix is applied to the substrate require careful optimization.
For many laboratories, MALDI is a tool of convenience
when analyzing complex samples. MALDI analyses have a
short turnaround time and often require very little sample preparation. For many complex samples, MALDI can provide the
desired analytical information, thereby eliminating the need
for other, more time-intensive analysis techniques. The versatility of MALDI, however, extends beyond simple determination of molecular weight. Combining MALDI MS and MS/
MS methodologies with novel software tools enables a variety
of different measurements, including identification and characterization of posttranslational modifications such as glycans
and glycoproteins,4-6 phosphopeptides,7-8 as well as disulfide mapping in proteins as large as antibodies.9 Using insource fragmentation, top-down sequencing can also be
carried out for small proteins, as well as determining >80%
sequence coverage for antibodies.10 Furthermore, detailed
analysis of fractionated samples has enabled liquid chromatography (LC)-MALDI workflows for a variety of proteomic
studies.11-12
In recent years, several advances in instrumentation and
methodologies have allowed MALDI to play a greater role
in discovering and developing new therapeutics. MALDI
instrumentation is becoming faster with laser speeds >10
kHz, sensitivities in the attomolar range, and resolution that
allows detection of small posttranslational modifications on
midsized proteins. These advances and future improvements will ensure that MALDI TOF plays a significant role
1

Bruker Daltonics, Billerica, MA, USA
SAMDI Tech, Chicago, IL, USA

Corresponding Authors:
Dale S. Cornett, Bruker Daltonics, PO Box 479, Fairview, TN 37062, USA.
Email: shannon.cornett@bruker.com
Michael D. Scholle, SAMDI Tech, 3440 South Dearborn St., Suite 220S,
Chicago, IL 60616, USA.
Email: mscholle@samditech.com

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Table of Contents for the Digital Edition of SLAS Discovery - Special Issue on Advances in MALDI Mass Spectrometry for Drug Discovery - Volume 22 Issue 10 - December 2017