Peptides, flexibility

Peptide libraries made up of millions of randomized peptide sequences have proven useful for the identification of novel ligands that may be of interest for the development of medicinally active compounds.[123,124] However, due to the short length of the individual peptides in linear peptide libraries, they possess considerable conformational flexibility and can populate multiple random-like conformations. This flexibility does not allow one to determine the precise three-dimensional orientation of the side chains, which greatly impedes structure-based design. These facts have greatly accelerated studies into conformationally restricted libraries, where constraints have been introduced to decrease peptide flexibility. However, what is really required is the design of conformationally defined and constrained templates for library display. These templates present the side chains of selected residues in a defined three-dimensional space. Thus, as an alternative to linear peptide libraries, the well-char-... 

Interactions with species external to the peptide chain (solvent, ion, another peptide chain or any other type of biomolecular environment) are also expected to guide backbone folding and impact peptide flexibility. In this scope, complexation of model peptides [46, 53, 55, 65, 73, 87, 90,100,102,120,124,129,136] shed light on the interface between a protein and its environment. 

R. C. Wade, M. E. Davis, B. A. Luty, J. D. Madura, and J. A. McCammon. Gating of the active site of triose phosphate isomerase Brownian dynamics simulations of flexible peptide loops in the enzyme. Biophys. J., 64 9-15, 1993. 

Proline is relatively compact because of the cyclic nature of its side chain It has less conformational flexibility than the other ammo acids and the presence of proline affects the shape of a peptide more than other ammo acids... 

Because it is desirable to break a peptide this way, some flexibility is required in the rigorous definition of sp -sp single bond. In particular, the dative Cqj-N bond in the backbone of a peptide is considered to be such a bond since the definition is based on the number of neighbors — four for carbon, three for nitrogen, two for Oxygen, etc. If this were not the case, you couldn t break a protein into classical and quantum regions at all. 

R Czermmski, R Elber. Reaction path study of conformational transitions m flexible systems Application to peptides. I Chem Phys 92 5580-5601, 1990. 

In a different approach, a TNF fusion protein designated TNF-Selectokine has been described [5]. This TNF prodrug is comprised of a trimeric scFv-TNF fusion protein to which a TNFR fragment has been fused at the C-terminal. A flexible peptide linker between TNF and the blocking receptor domain is comprised of sequences specifically recognized by tumor associated proteases such as tissue plasminogen activator, urokinase type plasminogen activator or... 

Polymer supported xanthene derivatives have been used in the solid phase synthesis of 1-aminophosphinic acids, RCH(NH2)PH(0)0H, <%TL1647> and of C-terminal peptide amides <96JOC6326>. Xanthene units also feature in crown ethers <96JCS(P2)2091>, calixarenes <96JOC5670> and in a flexible template for a P-sheet nucleator <96JOC7408>. 

Bcl-2 is one of the many factors that control apoptosis, and overexpression of Bcl-2 has been observed in many different cancers. A homology model of Bcl-2 was derived from the NMR 3D structure of the Bcl-XL complex with a Bak BH3 peptide. This model served to search the NCI 3D database of 206,876 organic compounds for potential Bcl-2 inhibitors, which bind to the Bak BH3 binding site of Bcl-2. Full conformational flexibility of the ligands was taken into account in the program DOCK. Thirty-five potential inhibitors were tested, and seven of them had IC50 values from 1.6 to W.OpM. One of... 

Some of their derivatives have been used as antiviral drugs. Due to their flexible chemistry, they can be exploited to design drug delivery systems and in molecular nanotechnology. In such systems, they can act as a central lipophilic core and different parts like targeting segments, linkers, spacers, or therapeutic agents can be attached to the said central nucleus. Their central core can be functionalized by peptidic and nucleic acid sequences and also by numerous important biomolecules. 

Locahzed motion can also lead to local variations in correlation times. Folded peptides with unfolded C- or N-terminal residues, for example, will have varying correlation times for the rigid and flexible parts of the molecule, resulting in different cross-relaxation rates. Such effects can usually be distinguished by the Unewidths and intensities of the corresponding diagonal signals, since the autorelaxation rates also depend on the correlation time. 

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