The International School of Crystallography held a course at the Ettore Majorana Centre in Erice in 1997 on “Direct methods for solving macromolecular structures”. In those days, Dual Space recycling methods, introduced by Hauptman and Weeks had allowed the breakthrough of extending atomic resolution phasing to macromolecules. The largest previously unknown macromolecule to have been phased by such methods was hirustasin at 1.2 Å resolution, with 400 independent atoms. At the time of the meeting, triclinic lysozyme at 1.0 Å, with 1,001 equal atoms was solved with SHELXD. Fifteen years later, ab Initio phasing has pushed the size and resolution limits of the problems it can tackle. Macromolecules with several thousands of atoms in the asymmetric unit can be solved from medium resolution data. One of the successful approaches is the combination of fragment location with the program PHASER and density modification with the program SHELXE in a supercomputing frame. The method is implemented in the program ARCIMBOLDO, described in this chapter

Our work is supported by the Spanish MICINN, CDTI and CSIC (Grants BIO2009-10576; IDC-20101173; predoctoral grants DR, IDM, IMdI; JdC to KM), Generalitat de Catalunya (2009SGR-1036)

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