Flexibility and rigidity, requirements for the function of proteins and protein pigment complexes

Abstract

Proteins may be rigid or flexible to various degrees as required for optimum function. Flexibility at the level of amino acid side-chains occurs universally and is important for binding and catalysis. Flexibility of large parts of a protein which rearrange or move are particularly interesting and will be discussed here. We differentiate between certain categories of large-scale flexibility although the boundaries between them are diffuse: flexibility of peptide segments, domain motions and order-disorder transitions of spatially contigous regions. The domains may be flexibly linked to allow rather unrestricted motion or the motion may be constrained to certain modes. The polypeptide segments linking the domains show characteristic structural features. The various categories of flexibility will be illustrated with the following examples. (a) Small protein proteinase inhibitors which are rather rigid molecules which provide binding surfaces complementary to their cognate proteases, but also show limited segmental flexibility and adaptation. (b) Large plasma inhibitors which exhibit large conformational changes upon interaction with proteases probably for regulatory purposes. (c) Pancreatic serine proteases which employ a disorder-order transition of their activation domain as a means to regulate enzymic activity. (d) Immunoglobulins in which rather unrestricted and also hinged domain motions occur in different parts of the molecule probably to allow binding to antigens in different arrangements. (e) Citrate synthase which adopts open and closed forms by a hinged domain motion to bind substrates and release products and to perform the catalytic condensation reaction, respectively. (f) The bifunctional multienzyme complex riboflavin synthase in which two enzymes (alpha and beta) catalyse two consecutive enzymic reactions. The beta-subunits form a shell, in which the alpha-subunits are enclosed. Diffusional motion of the catalytic intermediates is therefore restricted. In addition, segmental rearrangement occurs in the assembly of the beta-subunit. In contrast, rigidity is the dominant impression provided by the structures of the light harvesting complexes and the reaction centres involved the photosynthetic light reactions. These are large protein complexes in which the proteins serve as matrices to hold the pigments in the appropriate conformation and relative arrangement. Since motion would contribute to deactivation of the photo-excited states of the pigments and diminish the efficiency of light energy and electron transfer, a functional role for rigidity is easy to rationalize for these proteins.

Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers

“…The presence of strong (3× SD) peaks in the jF o j − jF c j coefficient electron density maps (Fig. 1C) confirms that the observed disordered density is not a crystallographic artifact and is analogous to previous reports of local or global dynamics within proteins (15) and protein•ligand (16) structures that manifest as either high individual atomic temperature factors (B factors) or discontinuous electron density (17). Finally, by occupancy refinement of only T3 (occupancy = 0.70) and 9c (occupancy = 0.99), we were able to remove the negative electron density on Author contributions: E.J.F.…”

Structural and Functional Evolution of Positively Selected Sites in Pine Glutathione S-Transferase Enzyme Family*

“…Rigidity is an important factor for the integrity of a protein native folded structure, whereas conformational flexibility is important for binding and catalysis of diverse substrates (49). Protein loop regions are relatively flexible compared with the ␣-helices and ␤-strands they connect.…”

NMR studies of mobility within protein structure

“…In the course of the article 1 observed that certain parts of the proteins could not be observed or were poorly shown in structures derived from X-ray diffraction data. At that time [and still to some degree] it was not possible to distinguish between motion and disorder in crystals [14]. Today it is common to discuss such problems in separate terms of Bfactors and disorder.…”

“…There is the danger that such studies will be treated as if they define a two-state switch (first-order phase change) in solution, but the objections to such an extrapolation are obvious and the process of molecular change is not likely to be so absolutely cooperative. The study of one molecule in two different crystal forms is, of necessity, the study of a first-order phase change [14]. Such a change is inherently slow and its nature in solution is likely to be very different.…”