Restricting Conformational Space

Heuberger and co-workers obtained, by using eSFA, a very intriguing result. Their data indicate that there exists a fine structure embedded within the established steric repulsion of PEG in the brush regime (Fig. 15) [159] arising due to restriction of the conformational space of the PEG/water complex, which causes quantisation of the steric force observed in the SFA. The presence of this water-induced restricted conformation space was suggested to have implications in protein adsorption since in order to adsorb a protein induces a local deformation, which necessitates a restriction of the PEG and protein conformational space, which is energetically and kinetically unfavourable [159, 160]. 

Taking into account the results of these ensemble calculations the backbone structure of microcystin-LR reveals a restricted conformational space in part of the ring backbone and significant flexibility in the rest, i.e. mainly involving the residues Mdha, D-Alai and Leu. Interestingly, by comparing the 3D-structures of the variant LR in DMSO and in DMSO/water the conformational differences are related to this sequence portion (110). 

While chemical similarity [970—973] is not easy to define on an objective basis (compare chapter 9.4), every medicinal chemist has some hypothesis or intuition how a pharmacophore can be extracted from the structures of a series of active molecules. Rational methods for the alignment of congeneric molecules are e.g. the active analog approach [882, 974 — 977] and the distance geometry method [31,926]. In the active analog approach large numbers of different conformations of the molecules are superimposed often only a few conformations are allowed for all molecules, which lead to a restricted conformational space for their common pharmacophore. 

Since we are interested in classifying conformational pseudophases of polymers with respect to their thickness, it is useful to introduce the restricted conformational space 7 = X rge(X) > p of all conformations X with a global radius of curvature larger... 

The canonical partition function of the restricted conformational space thus reads... 

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... 

The most serious problem with ensemble average approaches is that they introduce many more parameters into the calculation, making the parameter-to-observable ratio worse. The effective number of parameters has to be restrained. This can be achieved by using only a few confonners in the ensemble and by determining the optimum number of confonners by cross-validation [83]. A more indirect way of restraining the effective number of parameters is to restrict the conformational space that the molecule can search... 

Cys residues spaced i, i + 3 apart have been covalently linked to obtain cyclic peptides which fold into a 310-helix. Balaram et al.[159l synthesized Boc-c[-Cys-Pro-Aib-Cys-]-NHMe, wherein a disulfide bond links the two Cys residues. Pro and Aib residues were used to restrict conformational flexibility. NMR and X-ray diffraction studies revealed a highly folded, compact formation of an incipient 3i0-helix, with the S—S bridge lying approximately parallel to the helix axis. 

The P-tetralin amino acid induces the a-helical conformation by fixing the torsional angles along the peptide backbone at about -60° (< >) and -50° ( p).109 P-Tetralin amino acids may be regarded as cyclic-constrained phenylalanine analogues. As shown in Section II.A, this class of unnatural amino acids is known to stabilize distinct conformations in peptides since the two substituents at the a-cen-ter restrict the available conformational space. Cyclic a,a-dialkylated glycines and a-substituted alanines preferentially adopt a-helical conformations.205... 

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