Improved molecular replacement by density- and energy-guided protein structure optimization

DiMaio, F., Terwilliger T. C et al. Nature (2011)

We show that the crystallographic phase problem can be solved using distant evolutionary relationships by combining algorithms for protein structure modelling with those developed for crystallographic structure determination. Ingegrating Rosetta structure modelling with Autobuild chain tracing yielded high-resolution structures for 8 of 13 X-ray diffraction data sets that could not be solved in the laboratories of expert crystallographers and that remained unsolved after application of an extensive array of alternative approaches. We estimate that the new method should allow rapid structure determination without experimental phase information for over half the cases where current methods fail, given diffraction data sets of better than 3.2 Å resolution, four or fewer copies in the asymmetric unit, and the availability of structures of homologous proteins with  >20% sequence identity.