Molecular replacement with multiple different models

Classical molecular replacement methods and the newer six-dimensional searches treat molecular replacement as a succession of sub-problems of reduced dimensionality. Due to their `divide-and-conquer' approach, these methods necessarily ignore (at least during their early stages) the very knowledge that a target crystal structure may comprise, for example, more than one copy of a search model, or several models of different types. An algorithm for a stochastic multi-dimensional molecular replacement search has been described previously and shown to locate solutions successfully, even in cases as complex as a 23-dimensional 4-body search. The original description of the method only dealt with a special case of molecular replacement, namely with the problem of placing n copies of only one search model in the asymmetric unit of a target crystal structure. Here a natural generalization of this algorithm is presented to deal with the full molecular replacement problem, that is, with the problem of determining the orientations and positions of a total of n copies of m different models (with n ≥ m) which are assumed to be present in the asymmetric unit of a target crystal structure. The generality of this approach is illustrated through its successful application to a 17-dimensional 3-model problem involving one DNA and two protein molecules.