Conformation diversity

As the number of conformations increases exponentially with the number of rotatable bonds, for most molecules it is not feasible to take all possible conformations into account. However, a balanced sampling of the conformational space should be ensured if only subsets arc being considered. In order to restrict the number of geometries output, while retaining a maximum of conformational diversity, ROTATE offers the possibility of classifying the remaining conformations, i.c., similar conformations can be combined into classes. The classification is based on the RMS deviation between the conformations, either in Cartesian (RMS y 7if [A]) or torsion space in [ ], The RMS threshold, which decides whether two... 

James LC, Roversi P, Tawfik DS Antibody multispecificity mediated by conformational diversity. Science 2003 299 1362-1367. 

It is quite evident that the ferrous complexes of porphyrins, both natural and synthetic, have extremely high affinities towards NO. A series of iron (II) porphyrin nitrosyls have been synthesized and their structural data [11, 27] revealed non-axial symmetry and the bent form of the Fe-N=0 moiety [112-116]. It has been found that the structure of the Fe-N-O unit in model porphyrin complexes is different from those observed in heme proteins [117]. The heme prosthetic group is chemically very similar, hence the conformational diversity was thought to arise from the steric and electronic interaction of NO with the protein residue. In order to resolve this issue femtosecond infrared polarization spectroscopy was used [118]. The results also provided evidence for the first time that a significant fraction (35%) of NO recombines with the heme-Fe(II) within the first 5 ps after the photolysis, making myoglobin an efficient N O scavenger. 

Figure 8. IR and Raman OH stretching spectra of n propanol monomers and dimers reflecting conformational diversity. The Raman spectrum reveals the dominance of the internally hydrogen bonded Gt monomer most clearly, whereas the IR spectrum indicates more than five different dimer conformations in the red shifted dimer spectrum [69].

An improvement is to use a windowed RMSD function as a measure of the rate of conformation change. Specifically, for a given window length (e.g., 10 consecutive trajectory snapshots), the average of the all of the pairwise RMSDs (or alternatively, the average deviation from the average over that interval) is computed as a function of time. This yields a measure of conformational diversity over time, and can more readily reveal conformational transitions. 

M Kats, PC Richberg, DE Hughes. Conformational diversity and conformational transitions of a monoclonal antibody monitored by circular dichroism and capillary electrophoresis. Anal. Chem. 67 2943-2948 (1995). 

Cyclic Peptide Libraries with Conformational Diversity... 

In addition to sequential and chemical diversity, cyclic peptide libraries offer the possibility of conformational diversity where all components of the library differ from each other in their conformation, despite the identical connectivity. In this context two complementary approaches have been proposed, i.e. spatial screening based on head-to-tail cyclic peptides and cycloscan where the rest of the modes of cyclization are exploited. 

While in normal combinatorial peptide libraries (either chemical or phage display) each component has a unique sequence that is different from all others, in the cycloscan libraries all components have the same sequence, but differ in their conformation. This conformational diversity is generated in a dendrimeric hierarchy as shown exemplarily in Scheme 27 for the parent linear heptapeptide A-B-C-D-E-F-G. The diversity of the 1st order sublibrary (this nomenclature was adopted from Furka[468l) is based on the mode of cyclization. Excluding the head-to-tail cyclization there are seven different modes of cyclization that can be used for cycloscan three natural modes of cyclization and four modes of N-backbone cyclization. In addition there are five theoretical modes of C-backbone cyclization (see Scheme 1) which are not included in Scheme 27. 

Recent work has now shown the conformational diversity of inhibitors binding in the interdomain ATP-binding cleft [26]. Although the residues of the protein kinase catalytic core that form the bidentate donor-acceptor bond with inhibitors are identical throughout different structures, the residues of the inhibitors vary greatly. All inhibitors use this common bidentate bond yet the specificity lies in several other bonds formed between the inhibitor and specific regions of the individual protein kinases. Furthermore, it is difficult to model... 

Free energies of solvation in water and chloroform were calculated with the SM5.4/AM1 and SM5.4/PM3 models during a study on the effects of substitution of the hydroxyl group by the fluorine atom for (R,R)-tartaric acid derivatives. The results indicated that the substitution of OH by F results in greater conformational freedom of these compounds, and that solvation tends to decrease conformational diversity [18]. 

Valente, A. P., Miyamoto, C. A. and Almeida, F. C. (2006) Implications of protein conformational diversity for binding and development of new biological active compounds. Curr. Med. Chem. 13, 3697-3703. 

Cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. Owing to the robustness of amide bond chemistry, the ability to explore extensive chemical diversity by incorporation of unnatural and natural amino acids, and the ability to explore conformational diversity, through the incorporation of various constraints, arrays of cyclic peptides can be tailored to broadly sample chemical diversity. We describe the combination of a safety catch linker with a directed-sorted procedure for the synthesis of large arrays of diverse cyclic peptides for high-throughput screening. 

Characteristic of calix[n]arenes and their derivatives is the conformational diversity, which may cause difficulties in the synthesis of narrow rim derivatives (see Section IV), but also offers many additional chances to fine-tune the desired properties. Four basic conformations may be distinguished for a calix[4]arene [differing by the relative orientation of the (endo) OH and the p-positions] for which Gutsche introduced the names cone , partial cone , 1,2-alternate and 1,3-alternate (Figure 3). 

Lee S, Antony L, Hartmann R et al (2010) Conformational diversity in prion protein variants influences intermolecular beta-sheet formation. EMBO J 29 251-262... 

Chien P, Weissman JS (2001) Conformational diversity in a yeast prion dictates its seeding specificity. Nature 410 223-227... 

Every second protein domain in PDB is represented by more than one PDB entry 20% of proteins have two structures, and the remaining 30% more than two structures. Some of them are mutants (e.g., 400 of T4 lysozyme structures from Brian Matthews s laboratory) but in most cases, these multiple structures represent snapshots of the pocket conformational diversity. Furthermore, many entries contain more than one chain in an asymmetric unit. These protein structures related by noncrystallographic symmetry can also be used as a source of multiple pocket conformations. The noncrystallographic symmetry-related subunits increase the number of domains already represented by multiple experimental conformations from 50% to the overall level of 75% (Fig. 2). About 5% of the domains are represented by more than 30 copies. 

The absolute convergence time for the 4D docking procedure depends on the variability of the ensemble conformations and on the quality of their superimposition. When the receptor conformational diversity is restricted to local deviations, increasing the number of conformations does not lead to increase in the convergence time. 

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