Folded conformers

P. L. Privalov, Physical Basis ofi the Stability ofi the Folded Conformations ofi Proteins Protein Folding, Freeman, New York, 1992 K. A. DiU, Biochemistry 29, 7133 (1990). 

Implicit in the presumption of folding pathways is the existence of intermediate, partially folded conformational states. The notion of intermediate states on the pathway to a tertiary structure raises the possibility that segments of a protein might independently adopt local and well-defined secondary structures (a-helices and /3-sheets). The tendency of a peptide segment to prefer a particular secondary structure depends in turn on its amino acid composition and sequence. 

Crystallites occurring in PET fibers can assume two kinds of morphological forms. The first form represents the crystallite formed by molecules of folded conformation, while the other is formed from molecules of extended-chain conformation. The first form is sometimes called a flexural morphological form, whereas the other is called a straightened morphological form. The flexural form is the typical and prevailing morphological form in PET fibers. However, it should be stressed that no... 

It should be noted that the concept extended-chain crystal (ECC) does not mean a crystal, in which not a single molecule can form a told. ECC can contain some molecules with folded conformation but the folds play a role of defects... 

Some proteins contain covalent disulfide (S— S) bonds that link the sulfhydryl groups of cysteinyl residues. Formation of disulfide bonds involves oxidation of the cysteinyl sulfhydryl groups and requires oxygen. Intrapolypeptide disulfide bonds further enhance the stability of the folded conformation of a peptide, while interpolypeptide disulfide bonds stabilize the quaternary structure of certain oligomeric proteins. 

It was an outstanding experience to plan, organize and realize this book, and to work with such a distinguished group of contributors. I hope that the readers will enjoy the work they did. I won new friends during this book project, one of which is Pierre-Alain Carrupt. He prepared the cover graphics, which represents the molecular lipophilicity potentials for my PhD molecule verapamil in its extended and folded conformation. 

D. N. Brems, Solubility of different folding conformers of bovine growth hormone, Biochemistry, 27, 44541 (1988). 

Fig. 7. Stereoview of the crystal structure of water solvated host 5 (folded conformation). The structure is held together by host-host and host-solvent hydrogen bonding interactions. Within the solvation layer there are chains of circular H-bonds between the molecules of water (crystal data a - 8.227, b = 8.964, c - 16.945 A, a = 89.64, / = 97.51, y = 114.28°, space group Pi taken from Ref,3S>)...

Fig. 8. Stereoscopic illustration of the inclusion compound of host 5 (folded conformation) with acetic acid and 2 mol of water. Host-host and host-water hydrogen bonding interactions stabilize the structure. The solvation layers consist of cyclic carboxy dimers of acetic acid surrounded by water species (crystal data a = 7.857, b = 11.379,c = 13.831 A,a = 92.50,/i = 101.21, y = 101.12°, space group Pi taken from Ref. 351)...

However, recent application of two types of NMR methodologies that provide long-range structural information have painted a very different picture. From these experiments, the denatured state in 0 M urea and 8 M urea appear to be highly similar, both retaining the same overall spatial positioning and orientation of the chain seen in the folded conformation. 

Fig. 1. Schematic diagram of nuclease A131A in the folded conformation. The alpha helices and beta strands are labeled. NMR analysis suggests the two turns and one helix in black are modestly populated in the denatured state, whereas the shaded helix is slightly populated. Strands / l-/ 2-/ 3 form an extended structure about which littie is known. Reproduced from Barron, L. D., Hecht, L., Blanch, E. W., and Bell, A. F. (2000). Prog. Biophys. Mol Chem. 73, 1-49. 2000, with permission from Elsevier Science.

Although additional experiments and simulations are needed to determine how much of reality is captured in this model, it does explain one important property of proteins their rapid rate of refolding, which is independent of denaturation conditions. If the polypeptide chain is unable to escape from this steric trap and access conformations with the wrong topology, it could never wander far from the folded conformation and thereby avoid incorrect side chain/side chain interactions. 

Historically, research on polypeptide structure, whether by experimental or computational means, has focused on the folded state only. This is because an array of methods exist for detailed investigation of the folded state of a polypeptide, and because the folded state is commonly the functionally active one. There are, however, two scenarios in which a full characterization of the unfolded state becomes as essential as the determination of the folded conformation. The first is in the study of... 

In Section III, a distinction is made between experimental conformation and folded conformation. Thus, the most populated conformation of a peptide is identified as the folded conformation, irrespective of experimental or secondary-structure considerations. The folded state is then associated to the folded or most populated conformation, while the unfolded state embodies all other conformations and includes any other substates. 

Geometry errors increase with the size of a system when the number of nonbonded interactions increases, and folded conformations are differently affected than extended ones. That is, MP2-energies calculated at HF-geometries can be inaccurate, because geometry errors are not necessarily the same in different conformations of the same molecule. Regarding the molecular structures it can be shown that, even when differences between MP2 geometries and the HF equivalents are small, they can be significant. 

Three macrobicycles 40b (216), 40h (212), and 40k (211) were characterized by X-ray crystallography. Fig. 31 displays the structure of 40h. The compounds adopt a highly folded conformation, reminiscent of calixarenes (23) and related Schiff-base macrocycles (181). 

Based on the three-dimensional structure of CHS, we proposed that the initiation/elongation/cyclization cavity serves as a structural template that selectively stabilizes a particular folded conformation of the linear tetraketide, allowing the Claisen condensation to proceed from C6 to Cl of the reaction intermediate.14 In contrast, CTAL formation can occur either in solution or alternatively while sequestered in the enzyme active site. In either case, enolization of the C5 ketone followed by nucleophilic attack on the Cl ketone with either a hydroxyl group (in solution) or the cysteine thiolate (enzyme bound) as the leaving group results in CTAL. Similar lactones are commonly formed as by-products of in vitro reactions in other PKS systems.36 38... 

Figure 4-7. Folded conformation of the salen complex. Rs = Alkyl RL = aryl R1, R2 = FI, alkyl, or aryl R3 = bulky group. Reprinted with permission by Elsevier Science Ltd., Ref. 94. 

The mechanistic basis of 3 and 4 is a double application of the argument used for the YES operation with 1. Each receptor in 3 is capable of launching a PET process if the lumophore is powered up by ultraviolet excitation. In other words, the fluorescence of the 9-cyanoanthracene unit is efficiently quenched by either the amine or the 1,2-dioxybenzene group within the benzo-15-crown-5 ether unit. These quenching processes are predictable from thermodynamic calculations or from related bimolecular quenching experiments in the literature. The small separation of the amine from the lumophore ensures rapid PET kinetics. On the other hand, the presence of four bonds between the benzo-15-crown-5 ether and the lumophore is probably responsible for the incomplete quenching seen between this pair. No information is yet available regarding possible folded conformations of 3. 

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