Subject conformational flexibility

Like any other protein, the molecular structure of the prion is subject to conformational flexibility and to various thermal-induced fluctuations between varying conformational states. However, if these fluctuations permit the PrP conformation to be attained, then this abnormal conformer promotes the widespread conversion of PrP to PrP , leading to the precipitous deposition of the abnormal protein throughout the brain (mirrored by the rapid and relentlessly downhill clinical course). This pathological self-propagating shape conversion of a-helical PrP to P-sheet PrP may in principle be initiated by a seed PrP molecule in the neurotoxic conformation. This explains the transmissibility of prion diseases and accounts for how susceptible humans exposed to beef from an animal with mad cow disease develop variant Creutzfeldt-Jakob disease. 

Because of the profound influence that the overall shape of a polymer chain undoubtedly has on any orientation process, which involves rotation of the whole molecule, it is worthwhile digressing on the subject of equilibrium conformation. Flexible, linear polymers tend to be somewhat coiled-up in the liquid phase or in a solution. In a good solvent, polymer-solvent contacts are preferred energetically to polymer-polymer contacts and so the coils... 

The question arose whether there was a possibility of deriving improvements of our compound or to propose new lead compounds from comparison of the known molecules and some common properties. Since an X-ray structure of HIV-RT was not available at that time, we had to base our study on a comparison of properties of the inhibitor molecules alone. If such an approach includes molecules with conformational flexibility - as in 1 - a procedure of this type is easily subject to overinterpretation and must therefore be supported by experimental facts. This means that assumptions derived from a theoretical consideration should be checked by real test molecules before any conclusions can be drawn. 

The main difficulty for commonly used 3D descriptors results from the treatment of conformational flexibility. Considering that only a single conformation is inadequate for most classes of pharmaceutically relevant molecules, averaging over conformational space provides only a very rough view as to what is intended to be described, namely the possible arrangement of pharmacophoric groups in Cartesian space. In this section a more detailed view on three subjectively selected approaches to describe molecular similarity will be presented. The approaches have in common the fact that similarity is quantified to a less dependable degree from only the 2D structure or specific 3D conformations. 

The stereoselectivity of the hydride reduction of conjugated cyclohexenones has also been subjected to close examination from both experimental and theoretical viewpoints. Much of the work has involved polycyclic systems, e.g.. steroids which have little conformational flexibility and in which axial and equatorial directions of approach can be clearly defined. With small" hydride donors, these substrates show an even clearer preference for axial attack than the corresponding cyclohexanones. For examples involving reductions with lithium aluminum hydride and sodium borohydride, see Table 10. 3/(-Acetylcholest-5-en-7-one and cholest-2-en-l-one are notable in that the analogous saturated substrates are attacked from the equatorial direction115 l16. The reduction of 17/i-hydroxy-4-androsten-3-one (testosterone) to 4-androstene-3/1,17/j-diol with d.r. 90 10 can be compared with the sodium borohydride reduction of 17/i-hy-droxyandrostan-3-one (dihydrotestosterone) to androstane-3/ ,17/ -diol with d.r. 81 19 (see p 4030). 

As discussed in more detail in Section 11.13. the conformational flexibility and lability of the anion [N(S02CF3)2] (with significant delocalisation of charge) are associated with both frustration of crystallisation and low-melting points. The use of thermochemical and spectroscopic techniques has enabled the detection of polymorphs of salts of bis(trifluoromethanesulfonyl)amide [576]. However, relatively few have been subject to crystallographic characterisation. These include those of [CiC2pyr][NTf2l [389, 390], [Rmim]... 

Finally, there is a large body of experimental and theoretical contributions from investigators who are mainly interested in the dynamic and conformational properties of chain molecules. The basic idea is that the cyclisation probability of a chain is related to the mean separation of the chain ends (Morawetz, 1975). Up to date comprehensive review articles are available on the subject (Semiyen, 1976 Winnik, 1977, 1981a Imanishi, 1979). Rates and equilibria of the chemical reactions occurring between functional groups attached to the ends or to the interior of a flexible chain molecule are believed to provide a convenient testing ground for theories of chain conformations and chain dynamics in solution. 

Figure 8.5 gives the structure of the molecular subject of this classic study, decyloxybenzylideneaminomethylbutylcinnamate (DOBAMBC, 2). DOBAMBC possesses the archetypal FLC molecular structural features A rigid core with two flexible tails, one of which possesses a stereogenic center. A classic theoretical treatment of the SmC phase from 1978 by Durand et al. suggested that a zigzag conformation of the LC molecules is important.9... 

The majority of enzyme substrates contain flexible moieties. As the 3D structure of the substrate to be analyzed (the conformation) has a reasonable impact on the outcome of the method, a precise protocol is used to build it. Each substrate is subjected to a conformational search followed by energy minimization by means of a software developed at Molecular Discovery Ltd. The population of conformers is... 

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