Confonnational analysis

Polycyclic compounds are common, and many valuable sutMtances haiw fused-ring tstructures. For example, steroids, such as cholesterol, have four rings fus together—three six-membered and one five-mcmbered. Thin steroids look complicated compared with cyclohexane or decalin. the same principles that apply to the confonnational analysis of simple cyclohexane rings apply equally well (arH) often better) to steroida... 

Confonnational analysis of 4-thiohexofuranose derivatives having a- and /3-d-galacto and D-manno and a-D-talo configurations, has been carried out by Cicero and Varela " The anomeric substituent prefer a quasiaxial orientation and the bulky side chain tends to take a quasiequatorial disposition. 

An analysis of the energy changes that occur as a molecule undergoes rotations about single bonds is called a confonnational analysis. 

Figure 6. Qualitative confonnational analysis of the homo-DNA single strand backbone based on idealized conformations. Three simple criteria predict one single pairing conformation of a nucleotide uniL provided that the phosphodiester groups have a synclinal/ synclinal bond arrangement [2].

Figure 50. Qualitative confonnational analysis (cf. fig. 6,7, and 8 in lecture 1) predicts that the backbone of p-RNA has a single pairing conformation. This conformation belongs to an ensemble of (nine) least strained confcnmations.

Confonnational analysis methods. The approaches in this subdivision are half-way outside of the domain of automatic model builders and discussed in detail elsewhere (see Conformational Analysis 1 Conformational Analysis 2 and Conformational Analysis 3). However, most of the programs discussed below perform internally a conformational analysis of the whole molecule or parts of it and some programs are able to write multiple conformations of the molecule under consideration. 

In a different context, conformational analysis is essential for the analysis of molecular dynamics simulations. As discussed in Chapter 3, the direct output of a molecular dynamics simulation is a set of confonnations ( snapshots ) that were saved along the trajectory. These conformations are subsequently analyzed in order to extract information about the system. However, if, during a long simulation, the molecule moves from one... 

A similarity measure is required for quantitative comparison of one strucmre with another, and as such it must be defined before the analysis can commence. Structural similarity is often measured by a root-mean-square distance (RMSD) between two conformations. In Cartesian coordinates the RMS distance dy between confonnation i and conformation j of a given molecule is defined as the minimum of the functional... 

In this chapter we ll examine the confonnations of various alkanes and cycloalkanes, focusing most of our attention on three of them ethane, butane, and cyclohexane. A detailed study of even these three will take us a long way towar d understanding the main ideas of conformational analysis. 

Analysis of the conformations of other alkanes can be done in a similar manner. For any linear alkane the most stable conformation is the so-called zigzag conformation, which is anti about all of the carbon-carbon bonds. The zigzag confonnation for hexane follows ... 

Substituents in 2,4-position generaly prefer equatorial orientations in a chair confonnation of the six-membered ring. Bis-axial orientation of these substituents would lead to strong repulsion, but in some examples an axial-equatorial confonnation is observed, as will be disscussed below. The X-ray analysis of the 2,4-diaryl-3,7-dimethyl-l,5-dimethoxycarbonylbispidin-9-one (3) reveals a flattened chair-chair conformation with the aryl substituents, as expected, in the equatorial position. From comparison of the IR-, H-, and NMR spectra with those of the analoguous p-methoxyphenyl- and p-chlorophenyl-substituted derivatives, it follows that these all adopt a double-chair conformation (56). The same behavior was also found for the bispidones 14 and 35 (70) 46-48 and 104 (see Chart 16) (160). The PM3 calculations for various bispidones with aromatic substituents have shown that the cc confonnation is slightly more stable than the cb form, and this is much more stable than the bb conformation in all cases (161). 

Another application of substituent-based conformational analysis is pharmacophore searching. In the work of Olender and Rosenfeld, confonner hbraries of substituents are created with the attachment point to a central scaffold as the reference. To search the virtual library with minimal enumeration, they first apply a series of filters to eliminate most of the possibiUties. First conformers that clash when attached to the scaffold are removed, followed by substituents that do not contain any of the features speeifled in the pharmacophore queries. The next filter looks at pairs of substituents, to remove rotamers that cannot meet the distance constraints, followed by triples and so on. Using this hierarchy of filters, most rotamers/substituents ean be eliminated quiekly, leaving a small nrnnber to be enumerated and tested explieitly. A library based on five scaffolds with six substituents, each with 143 rotamers (equivalent to 10 entries), was scanned with a six-point pharmaeophore in a few hours. 

Analysis of the shape of the orienting potential, which constrains the preferred orientation of the effective axis of internal rotation of the tethered nitroxide, revealed the presence of two different conformations of the spin-label moiety. In order to explain these results, the quantum chemical procedure was utilized. The spin-label moiety in the polymer system was reduced to 4-acetamido-2,2,6,6-tetramethylpiperidine-l-yloxyl (II) (spin label plus tether). The molecule was subjected to a search for stable confonn-ers, which resulted in the two minima corresponding to the structures Da and nb." ... 

F re 4 illustrates the apparent viscosity for copolymer series IV as a function of polymer concentration and degree of ionization (a) of the 2 mer unit as determined by potentiometric titration with NaOH (data not shown). In the protonated form (a-1), the polymer should assume a conformation resenibling that of series III. Analysis of the panels in Figure 4, reveals an erqxmded conformation at high degrees of ionizatioiL Similarly, as the incorporation of the sulfobetaine monoma increases, the polymer chain assumes a more coUiq>sed confonnation as... 

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