X-ray crystallography is a powerful tool for determining the three-dimensional structures of macromolecules. Such structural information is extremely useful in understanding the biochemical properties and the biological functions of proteins and DNA. Three major methods are currently available for X-ray structure determination of biological macromolecules multiple isomorphous replacement (MIR), multiple-wavelength anomalous diffraction (MAD), and molecular replacement (MR). This projectl will focus on developing new techniques and computer software for the molecular replacement method. The MR method solves new protein structures using the atomic model of a homologous protein as the starting point. Rotation and translation functions are calculated to correctly orient and position this search model in the crystal. The remarkable success of protein crystallography and NMR has led to the elucidation of many unique protein structures protein folds), such that a new protein of interest oftentimes displays some degree of amino acid sequence homology to a protein of known structure. The MR method so far works best when the amino acid sequence homology is high, but generally has had only limited success in the more common cases of lower homology. Many new techniques have been developed in recent years in attempts to enhance the capability of this important method of protein structure determination. Further developments are still needed, and possible, to make the MR method even more powerful. Successful developments in this area can increase the productivity of the entire crystallography community. The specific aims of the current research project are the development of new techniques for - I. deriving more appropriate search atomic models; 2. obtaining better rotation function results; 3. obtaining better translation function results; 4. better combination and automation of the rotation and translation function searches. The overall goal of this project is the development and maintenance of a new and user-friendly computer software package that incorporates these new techniques. This software will be made available to the entire crystallography community.
