Following molecular structure and dynamics in real time using femtosecond stimulated Raman spectroscopy

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To understand function, study structure . Francis Crick made this statement after his elucidation of the structure of DNA revolutionized not only the scientific community but also society as a whole. While it was made with the microscopic world in mind, it is equally true in our day-to-day macroscopic world. If we were presented with a car engine and asked to investigate how it functions we would probably do two things: Firstly, we take it apart to find out what it consists of, how it is constructed and which parts are moving. Secondly, we might change the fuel, play with the electronics and connect and disconnect any cables we may find to gain insight into which parts are essential and what their function is. In many ways, proteins, the work horses of our body, are a microscopic equivalent of that car engine, except that they usually are much more complex and more importantly, much more efficient at what they do. To understand their function, we use the same approach outlined above. We try to learn as much as possible about their structure using various spectroscopic techniques and change various parts of the protein, its environment and fuel to determine how it works. The only thing we usually cannot do is to watch them do their work in real time. How important this is, is best demonstrated by the inner workings of a watch. Looking inside a dead watch makes it difficult to understand how it works, but watching all the parts move makes it much easier. These concepts are equally true for protein function as for the structural changes associated with chemistry in general.The fundamental problem in observing how atoms rearrange during a (bio)chemical process is that they move incredibly fast, usually on the time scale of femtoseconds. (To put this in perspective: one femtosecond compares to five minutes as five minutes to the existence of the universe.) It is thus necessary to create a camera to capture structural snapshots of the reacting species as the chemical change proceeds. Molecules consist of atoms that are held together by electronic bonds. The motions of these atoms are usually described by molecular vibrations. Since the strength of these bonds is closely connected to the three-dimensional structure of the molecule, it is possible to follow any changes in structure by recording the energy of molecular vibrations as a function of time. Traditionally, such techniques have been orders of magnitude too slow to directly observe molecular change. To achieve this goal I would like to establish novel spectroscopic techniques based on vibrational spectroscopy using femtosecond laser pulses that enable the observation of molecular structure in real time. These techniques will be based on recent results suggesting that the limits established by the uncertainty principle can be circumvented to achieve the necessary temporal and energy sensitivity.This ability should enable me to address many fundamental questions in the, biologically relevant, condensed phase such as: how is energy redistributed throughout a molecule? what is the role of the solvent in guiding a photochemical process? how are enzyme-substrate complexes formed and what are their structural and temporal dynamics? In analogy with the above comparison: I hope to visualize the moving pistons of biochemical and chemical reactions.