Mass Spectrometry Research at WU


Professor Michael Gross is a world-reknown expert in the field of mass spectrometry. His research group in the Department of Chemistry (and the Department of Internal Medicine at the Medical School) at Washington University uses mass spectrometry to study protein-ligand interactions and DNA-ligand interactions. A ligand is a molecule that binds to another molecule and in the case of binding to DNA or a protein, the ligand binding event usually changes the activity (chemical behavior and reactivity) of the protein or DNA molecule. Thus, the work that is done in Professor Gross' lab is important for understanding a number of key biochemical and biophysical phenomena.

In a study that was recently reported in the Journal of the American Chemical, Professor Gross' group characterized the binding of metal cations such as K+, Li+ and Sr2+ to DNA structures. Specifically, they investigated the binding of these ions to a DNA structure called a Guanine Quadraplex (shown in Figure 1). These Guanine Quadraplex (G-quadruplex) structures are of interest because they are localized in a part of the chromosome called the telomere. Stabilizing these telomeric structures (by binding of ions or other molecules) makes it harder for the DNA to replicate. Rapid cellular replication (which requires replication of the DNA) is a hallmark of cancer cells. Cancer cells grow and divide in an uncontrolled fashion. In their study, Professor Gross' group determined that the guanine quadraplex appears to bind one or multiple K+ ions depending on the overall charge of the G-quadruplex. One strategy to prevent replication of cancer cells might be to design a compound that binds specifically to this DNA motif.

In this mass spectrometry study, Professor Gross determined the number of K+ ions that bind to the G-quadruplex. Figure 2 shows the mass spectrum of complexes between DNA and potassium ions. Professor Gross concluded that these G-quadruplex structures can bind one or more than one (two, three, or four or more) potassium ions when the total charge on the DNA-potassium complex is -3 or -4 (some of these peaks are labeled in boldtype on Figure 2).

These types of studies are adding to our fundamental understanding of the complex electrostatic interactions in DNA and other biologically important molecules (proteins, RNA, etc.). Electrostatic interactions, as well as other inter- and intramolecular forces will be studied in Chemistry 111.

Figure 1. The Guanine Quadraplex (G-quadruplex) structure that occurs in telomeric DNA. It consists of 4 guanine bases.

 

Figure 2. Mass spectrum of DNA-potassium ionic complexes. The x-axis shows mass-to-charge ratio and the y-axis shows the relative amplitude (RA) of each peak (the amplitude of the highest peak is set equal to 100. The mass-to-charge ratios of a series of peaks that have a total charge = -4 are indicated in bold type on the spectrum. From: J. Amer. Chem. Soc. 125: 42-43 (2003).


Application Question: Consider the mass spectrum shown in Figure 2 and decide how you might conclude that the series of peaks represent DNA-potassium complexes that differ only in the number of potassium atoms bound to the G-quadruplex. Focus specifically on the series of peaks labeled in bold type on the figure. [A subtle point that was not mentioned in the earlier discussion, and that you will need to answer this question is that mass spectrometry actually measures the mass-to-charge (m/q) ratio of a given chemical species. If the charge on the species in this set of peaks is -4 (q = 4), you might consider what difference in mass is required to get the observed variation in m/q in this series of peaks.]

Answer


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