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Relationships among amino acids determine stability and function and are also constrained by evolutionary history. We develop a probabilistic hypergraph model of residue relationships that generalizes traditional pairwise contact potentials to account for the statistics of multi-residue interactions. Using this model, we detected non-random associations in protein families and in the protein database. We also use this model in optimizing site-directed recombination experiments to preserve significant interactions and thereby increase the frequency of generating useful recombinants. We formulate the optimization as a sequentially-constrained hypergraph partitioning problem; the quality of recombinant libraries with respect to a set of breakpoints is characterized by the total perturbation to edge weights. We prove this problem to be NP-hard in general, but develop exact and heuristic polynomial-time algorithms for a number of important cases. Application to the beta-lactamase family demonstrates the utility of our algorithms in planning site-directed recombination.