Extension of molecular replacement: a new search strategy based on Patterson correlation refinement

A new search strategy is presented to obtain initial phases for single-crystal diffraction data by molecular replacement. It consists of carrying out 'Patterson refinements' of a large number of the highest peaks of a rotation function. The target function for Patterson refinement is proportional to the negative correlation coefficient between the squared amplitudes of the observed and the calculated normalized structure factors. If the root-mean-square difference between the search model and the crystal structure is within the radius of convergence of the minimization procedure employed, the correct orientation can be identified by having the lowest value of the target function after refinement. Similar to conventional crystallographic R-factor refinement, the target function for Patterson refinement may be combined with an empirical energy function describing geometric and non-bonded interactions. Patterson refinement of individual atomic coordinates or of rigid-group parameters may be carried out. Search models of crambin and of myoglobin with 1.6-2.0 Å backbone atomic r.m.s, differences from the target crystal structures show that the Patterson refinement strategy can solve crystal structures that cannot be solved by conventional molecular replacement or even by full six-dimensional searches.