FEATURE ARTICLE
Biomolecules and Nanotechnology
Evolution has forced innovative solutions to biomolecular problems. Some may inform the growing field of nanotechnology
David Goodsell
Symmetry of Proteins
The process of evolutionary selection has yielded an unusual result: Evolution of proteins favors perfect symmetry. The majority of soluble and membrane-bound proteins found in cells are symmetrical complexes formed by several subunits. Most proteins are oligomeric, composed of multiple copies of one or more types of subunits. Nearly all of these oligomeric proteins are also beautifully symmetrical, with identical subunits packed in identical environments. A complex interplay of conflicting functional needs has driven evolution to this surprisingly aesthetic conclusion.
The major evolutionary force is the need for large proteins. Large proteins are preferred over smaller proteins and peptides for several reasons. Some functional roles simply require a molecule that is physically big. Large protein complexes form structural elements that span entire cells; they form rings that encircle DNA and rulers that measure lengths of DNA; they create pores of many sizes through cell membranes; they form large spherical containers for storage and delivery and small cylindrical containers that create exactly the proper environment for protein folding.
Large proteins are also well suited for cooperative functions, such as allostery (discussed below) and multivalent binding, which require a molecule with several identical active sites. Multivalent binding increases the binding strength of a molecule to a target by reduction of entropy. Once one site on the protein has bound, the other sites are held in close proximity to the target, increasing their probability of binding. Many of the molecules of the immune system have a distinctive shape, composed of many flexible arms, in order to take advantage of this cooperativity.
Large proteins also have attractive physicochemical characteristics. They are more stable against denaturation, having a more stabilized internal structure than small proteins. Large proteins also have a lower ratio of surface area to volume, making them less prone to damage and degradation by other enzymes.
Unfortunately, the accuracy of the protein-synthetic machinery limits the size of proteins that may be constructed. As noted above, protein chains of 300 to 500 amino acids may be consistently synthesized, but longer chains will become increasingly riddled with errors. The answer is to build a complex from subunits when a large protein is needed, which allows any faulty subunits to be discarded. This also allows new possibilities for regulation: Large structures may be built and disassembled at will, or subunits may be transported to a distant site (or even outside the cell) and assembled there.
Nearly all of these oligomeric proteins in cells form closed, symmetrical complexes based on ideal point-symmetry groups. In general, if a complex contains several identical subunits, they will adopt identical symmetrical positions in the complex. Asymmetric complexes and random aggregates are almost completely unknown. Symmetrical association is favored over asymmetric association because it provides stability and control. The stability of closed, symmetrical complexes is a consequence of two factors. First, interfaces between proteins are highly specific and highly directional, so in most cases evolution selects and improves only a single type of association between subunits. Second, given these specific, directional interfaces, the maximum number of intersubunit contacts is formed by closed complexes.
Closed, symmetrical complexes also ensure that the level of oligomerization is tightly controlled. Unwanted aggregation is very dangerous for cells?pathological aggregation of mutant proteins leads to diseases such as sickle-cell anemia, Alzheimer's disease and prion-related diseases. Selection of a closed, symmetrical complex defines the size and shape of the resultant complex.
Under special circumstances, symmetry may be broken for a given functional need. For instance, viruses often need to build shells that are too large to construct with typically sized proteins in perfect symmetry?the highest point-group symmetry is icosahedral, so the largest perfectly symmetrical capsid is limited to 60 subunits. If larger shells are needed, more subunits must be used.
Viruses often turn to quasisymmetrical complexes, where hundreds to thousands of identical subunits combine in similar, but not perfectly symmetrical, positions. Quasisymmetry was first conceived as a method of tiling an icosahedron with a triangular network, much like the geodesic domes designed by Buckminster Fuller. Protein subunits are arranged in this triangular lattice. Small elastic deformations allow the subunits to adopt similar contacts in each of the different positions. A series of different networks can be defined containing 60T subunits, where T is a "triangulation number." Only certain triangulation numbers yielded smooth networks, according to the relation T = h2 + hk + k2, where h and k are integers.
When structures were obtained for viral capsids, this model for quasiequivalence was surprisingly successful. The arrangement of subunits of most capsids corresponded closely to one of the triangulation numbers: Examples with T = 1 (perfect icosahedral) symmetry and T = 3 symmetry are shown in Figure 7. However, elastic deformations were not observed. Instead, subunits typically accommodated different positions through the use of structural "switches," where the subunit adopts two or more significantly different conformations. Often, the subunits are composed of two domains connected by a flexible linker, and flexure of the subunit is used to adopt different conformations.
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