The majority of protein oligomers form clusters which are nearly symmetric. Understanding of that imperfection, its origins, and perhaps also its advantages requires the conversion of the currently used vague qualitative descriptive language of the near-symmetry into an accurate quantitative measure that will allow to answer questions such as: "What is the degree of symmetry deviation of the protein?," "how do these deviations compare within a family of proteins?," and so on. We developed quantitative methods to answer this type of questions, which are capable of analyzing the whole protein, its backbone or selected portions of it, down to comparison of symmetry-related specific amino-acids, and which are capable of visualizing the various levels of symmetry deviations in the form of symmetry maps. We have applied these methods on an extensive list of homomers and heteromers and found that apparently all proteins never reach perfect symmetry. Strikingly, even homomeric protein clusters are never ideally symmetric. We also found that the main burden of symmetry distortion is on the amino-acids near the symmetry axis; that it is mainly the more hydrophilic amino-acids that take place in symmetry-distortive interactions; and more. The remarkable ability of heteromers to preserve near-symmetry, despite the different sequences, was also shown and analyzed. The comprehensive literature on the suggested advantages symmetric oligomerizations raises a yet-unsolved key question: If symmetry is so advantageous, why do proteins stop shy of perfect symmetry? Some tentative answers to be tested in further studies are suggested in a concluding outlook.

The majority of proteins form oligomers which have rotational symmetry. Literature has suggested many functional advantages that the symmetric packing offers. Yet, despite these advantages, the vast majority of protein oligomers are only nearly symmetric. A key question in the field of proteins structure is therefore, if symmetry is so advantageous, why do oligomers settle for aggregates that do not maximize that structural property? The answer to that question is apparently multi-parametric, and involves distortions at the interaction zones of the monomer units of the oligomer in order to minimize the free energy, the dynamics of the protein, the effects of surroundings parameters, and the mechanism of oligomerization. The study of this problem is in its infancy: Only the first parameter has been explored so far. Here we focus on the last parameter–the mechanism of formation. To test this effect we have selected to focus on the domain swapping mechanism of oligomerization, by which oligomers form in a mechanism that swaps identical portions of monomeric units, resulting in an interwoven oligomer. We are using continuous symmetry measures to analyze in detail the oligomer formed by this mechanism, and found, that without exception, in all analyzed cases, perfect symmetry is given away, and we are able to identify that the main burden of distortion lies in the hinge regions that connect the swapped portions. We show that the continuous symmetry analysis method clearly identifies the hinge region of swapped domain proteins–considered to be a non-trivial task. We corroborate our conclusion about the central role of the hinge region in affecting the symmetry of the oligomers, by a special probability analysis developed particularly for that purpose.