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The PHENIX Substructure Search Procedure. Ralf Grosse-Kunstleve and Paul Adams, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, BLDG 4R0230, Berkeley, CA 94720.

Isomorphous replacement and anomalous difference experiments are the most powerful techniques known today for phasing macromolecular structures without prior knowledge of stereochemistry. Essential to these techniques are methods for solving the heavy atom substructure or anomalously scattering substructure. As part of the PHENIX¹ package (Python-based Hierarchical Environment for Integrated Xtallography) we have implemented a novel substructure search procedure integrating the use of Patterson functions, fast translation functions, Sayre squaring (direct methods in real space), and a random-omit procedure similar to that in SHELXD². We used the procedure successfully for solving substructures containing up to 66 sites in the asymmetric unit.

The use of the fast translation functions is facilitated by two important improvements compared to our earlier implementation³. Making use of David Langs' recently published observation⁴ we were able to reduce the memory requirements for the fast translation function by almost an order of magnitude. The second major improvement is the automatic transformation of centred settings to primitive settings. For F-centred space groups this leads to a speed-up of more than two orders of magnitude.

Currently the integrated procedure is entirely implemented in the Python scripting language, using the Computational Crystallography Toolbox⁵ (cctbx) as a foundation. Exploiting the flexibility of Python we were able to quickly try many different approaches. Although the runtime performance of our scripts is by no means prohibitive, we are planning to re-implement some components in a compiled language as we move to production mode. In this respect the development of our procedure serves as an example of modern hybrid programming⁶.