Crystallography at subatomic resolution permits the observation and measurement of the non-spherical character of the atomic electron density. Charge density studies are being performed on molecules of increasing size. The MOPRO least-squares re®nement software has thus been developed, by extensive modi®cations of the program MOLLY, for protein and supramolecular chemistry applications. The computation times are long because of the large number of re¯ections and the complexity of the multipolar model of the atomic electron density; the structure factor and derivative calculations have thus been parallelized. Stereochemical and dynamical restraints as well as the conjugate gradient algorithm have been implemented. A large number of the normal matrix off-diagonal terms turn out to be very small and the block diagonal approximation is thus particularly ef®cient in the case of large structures at very high resolution.

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