Research Interests

The Phase Problem

Crystallography is a powerful tool for determining the three-dimensional atomic structures of molecules.  In a crystallographic experiment, a crystalline sample is irradiated (most commonly by X-rays), and the radiation, which is wavelike in nature, is scattered to produce a diffraction pattern.  Each scattered wave has associated with it a magnitude, which is experimentally measurable, and a phase, which is not.  In order to visualize the molecules responsible for the scattering, the values of the phases must be found.  My work involves the development of mathematical techniques, known as direct methods, for deriving the phase values from the measured magnitudes and solving the "phase problem".

Direct methods were first used to determine small molecule structures, but in recent years they have proven to be very useful for finding parts (known as substructures) of large protein molecules.  Once a substructure is located, it can serve as a starting point or "bootstrap" for finding the rest of the protein molecule.  Suitable substructures can be prepared by making derivative crystals either by soaking native crystals in solutions containing atoms of heavy elements like mercury or by using the techniques of molecular biology to introduce selenium atoms into protein molecules in place of naturally occurring sulfur atoms.

Neutron Crystallography

Not all protein structures can be solved using existing X-ray diffraction techniques.  The goal of my current research is to develop new methods that use neutron radiation.  An important difference between X-ray and neutron diffraction involves the scattering from hydrogen atoms.  Hydrogen is normally found in nature as the isotope protium, but a small percentage of hydrogen atoms are present as the alternative isotope, deuterium.  These two isotopes scatter X-rays the same way, but neutrons are scattered differently.  This difference can be used as the basis for making ideal derivatives and solving protein structures.  I am working with collaborators in France and Japan who are developing the technology for deuterating selected parts of protein molecules and for measuring very accurate neutron diffraction data.