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Weight Watching of Molecules

Oliver Trapp
Department of Chemistry
Stanford University
June 2003

I develop a new and very efficient instrument to weigh and identify molecules. Knowing the mass of a molecule is an important means to clarify its structure and function in a biological system. The use of this instrument will help to speed up our understanding of diseases in the near future, and will eventually allow us to develop more efficient drugs.

The technique to weigh molecules is based on the flight-time of charged molecules in an electric field, which is mass dependent: small molecules fly faster than big ones. This principle can be compared to a person throwing stones: larger, heavier ones will fly a shorter distance than smaller, lighter ones. To weigh molecules, I am developing a new instrument currently called a time-of-flight mass spectrometer.

To determine a molecule's flight-time, it is necessary that all molecules start to fly at the same time and to wait until all molecules have reached their goal before the next molecules can start again. In most conventional systems, about 95% of the molecules are lost during this time because they are arriving at the start point while the molecules which started at the previous start time have not yet reached the detector. The consequence is that these molecules are not seen by the mass spectrometer and therefore their information is lost. This is a big problem, especially if time-of-flight mass spectrometry is coupled to any kind of separation, where molecules are entering the mass spectrometer in a fast and continuous analyte stream.

To solve this problem, my co-workers and I are using a completely different approach to develop a new instrument. The principle can be explained by a simple example: for an efficient transmission of a voice message (which can be regarded as a continuous stream of data) from one phone to another, it is necessary to encode and decode these complex signals. It is remarkable that complex mathematical algorithms for these procedures were already derived in the last century, but their use was not implemented until the development of computers. Nowadays such calculation procedures are very common in cellular phone communication techniques.

In my experiment, I make use of a mathematical model called a Hadamard transformation. First, I generate a continuous stream of charged molecules which are accelerated and focused by applying electrical fields in the instrument. This stream of molecules is then modulated with a series pf "beam on" and "beam off" states by applying a known random sequence based on the Hadamard matrix. This matrix allows to pulse the molecules in a well defined special pattern. The instrument records this modulated stream of ions instead of a single pulse. To get the flight-time of molecules, a reverse transformation with the known Hadamard sequence is performed. As the molecule stream never stops, 100% of all molecules are detected. Another advantage is that the speed of getting information about molecules is almost increased by a factor of 300 compared to conventional instruments because more spectra can be collected in the same amount of time.

This new instrument allows us to obtain more than only the information about the weight of a molecule to identify it. The molecules can tell us a very fascinating story by flying through the time-of-flight mass spectrometer. By selecting our samples wisely, we can not only learn about the structure and chemical composition, which is the kind of atoms these molecules are formed from and how these atoms are connected , but also the function of these molecules, their environment, and even their origin.

This information is very valuable, for example to study the interaction and function of bio-molecules in the human body. The skills needed to understand this language is a very challenging task. The whole analytical process can be compared to composing letters to words, which in our case is done by the mass spectrometer, and finally composing words to literature, which needs skilled scientists evaluating and integrating new data to already known pathways in biology and chemistry.