Crystallographic medium resolution

Key words Macromolecular Complementarity, Docking, Electron Density, Crystallographic Medium Resolution, Critical Points, Genetic Algorithms... 

The use of dissociable diastereomers for enantiomer resolution may be illustrated by the case where racemic mandelic acid is resolved using en-antiomerically pure a-methylbenzylamine. The n and p salts of a-methylbenzyl-amine mandelate have aqueous solubilities of 49.1 and 180 g/L, respectively, at 25°C [153], A more recent example, which focuses on the crystallographic origin of the solubility differences, is provided by the resolution of ( )-mandelic acid with (-)-ephedrine in water or methanol solution [154], In general, the relative solubilities of the n and p salt pairs are strongly influenced by the choice of solvent medium and temperature, which provide considerable flexiblity in optimizing the crystallization conditions and the efficiency of resolution. This process may be facilitated by the development of a full solubility phase diagram. 

Of great interest to the molecular biologist is the relationship of protein form to function. Recent years have shown that although structural information is necessary, some appreciation of the molecular flexibility and dynamics is essential. Classically this information has been derived from the crystallographic atomic thermal parameters and more recently from molecular dynamics simulations (see for example McCammon 1984) which yield independent atomic trajectories. A diaracteristic feature of protein crystals, however, is that their diffraction patterns extend to quite limited resolution even employing SR. This lack of resolution is especially apparent in medium to large proteins where diffraction data may extend to only 2 A or worse, thus limiting any analysis of the protein conformational flexibility from refined atomic thermal parameters. It is precisely these crystals where flexibility is likely to be important in the protein function. 

The X-ray crystallographic sturcture of the specific macromolecular receptor is the best starting point for designing a ligand for it. Over 300 X-ray crystal structures of proteins and nucleic acids have now been solved, including several ligand-macromolecule complexes (55) most of these are available in the Brookhaven Protein Data Bank (14). NMR is also now providing the equivalent of medium ( 3 A) resolution structures for proteins up to about 100 residues (15-17, 56). 

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