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Oligomeric protein interfaces involve non-covalent attractive forces plus potential steric entanglement. 70 years ago, Crick proposed a “Knobs in Holes” model for coiled-coil protein interfaces. Subsequently, modifications to this model have been proposed, describing either a “leucine zipper”, “jigsaw puzzle”, or a “peptide Velcro” interface. These principally describe forms of steric entanglement that may enhance oligomer stability. However, such entanglement has not been rigorously evaluated since it is not possible to experimentally eliminate intrinsic non-covalent attractive forces. 3D printing provides a novel means to evaluate steric entanglement of protein interfaces in the absence of attractive forces. Surprisingly, quantitation of the energy required to dissociate various coiled-coil protein interfaces of 3D printed protein models suggests minimal steric entanglement. Conversely, evaluation of domain-swapped interfaces of symmetric protein oligomers, differing by circular permutation, identifies extensive potential steric entanglement. Combined with available experimental data, the results suggest that steric entanglement of a protein interface can contribute to kinetic trapping of both folding and unfolding pathways. Steric entanglement of protein interfaces is therefore postulated to be an undesirable property for naturally evolved and designed protein oligomers.
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