6. Differences in Techniques for Small and Large Molecules

		Smaller molecules	Macro molecules
1.	Data collection	Diffract well to high resolution. Generally stable in air. Mount dry on fibre unless unstable. Several thousand reflections.	Diffract to lower resolution (some to higher resolution). Generally unstable to drying. Mount in capillary with mother liquor. Tens of thousands of reflections or more.
2.	Structure solution	Patterson, heavy atom or direct methods. One crystal only.	Isomorphous replacement. This involves many crystals. Heavy atom derivatives required.
3.	Refinement of structure	Full matrix least squares methods. Hydrogen atoms located.	Fitting of polypeptide or polynucleotide chain to electron density map. Constrained and/or restrained least squares methods. Hydrogen atoms not located. Most carbon atoms are also not well-defined except for high-resolution studies.