Alternative conformations

To obtain qualitative information about a molecule, such as its moleculip orbitals, atomic charges or vibrational normal modes. In some cast semi-empirical methods may also be successfully used to predict energy-trends arising from alternate conformations or substituent effects in qualitative or semi-quantitative way (but care must be taken in this area). 

Fig. 6 Superimposition of inhibitors and key active site residues from crystal structures of oseltamivir carboxylate 18 brown carbons, PDB - 2qwk) and Neu5Ac2en 4 (green carbons, PDB - IfSb) in complex with influenza A virus siaMdase. Note the alternative conformations of the...

The literature/X-ray data was sparse (-1000), so the information content was amplified by generating vast numbers of alternative conformations (-10 ) with a 64-node Linux cluster. Typically, we were able to generate 1 distinct conformation per compound in an average of <1 per minute. At critical points during the drug discovery process, such as when new structural data was obtained, we retrained our free energy model to improve its performance. 

Stability requirements for the existence of these alternative conformational states at Tg allowed us also to estimate the strength of their coupling to the regular lattice vibrations, which is determined by Tg, the material mass density, and the speed of sound. This enabled us to understand the universality of the phonon scattering at the low temperatures. 

Polar effects appear to be important for 3 -alkoxy substituents in enolates. 3-Benzyloxy groups enhance the facial selectivity of /(-boron enolates, and this is attributed to a TS I in which the benzyloxy group faces toward the approaching aldehyde. This structure is thought to be preferable to an alternate conformation J, which may be destabilized by electron pair repulsions between the benzyloxy oxygen and the enolate oxygen.109... 

Kelly JW (1996) Alternative conformations of amyloidogenic proteins govern their behavior. Curr Opin Struct Biol 6 11-17. 

Thermal 1,5-hydrogen shifts are thus allowed and, because of the symmetry of the T.S. (39), the H atom in the product (37, x = 1) will be on the same side of the common plane of the polyene s carbon atoms as it was in the starting material (36, x = 1) this is described as a suprafacial shift. This latter point would not be experimentally verifiable in the above example, but that thermal 1,5-shifts (which are quite common) do involve strictly suprafacial migration has been demonstrated in the compound (40). This is found, on heating, to yield a mixture of (41) and (42), which are produced by suprafacial shifts in the alternative conformations (40a) and (406), respectively ... 

Figure 5.7 Structures of the alternative conformations of the iron-binding sites in the orthorhombic crystal form of the recombinant N-lobe of human transferrin. Reproduced with permission from MacGillivray et ah, 1998. Copyright (1998), American Chemical Society. 

Conformational analysis of diastereomeric pyrido[ 1,2-/ ][ 1,3 oxazin-l -ones 91 and 92 revealed that 91 adopted an O-inside m-fused conformation, whereas 92 existed in a /ram-fused form <1996SL100>. Both isomers contained the C-8 substituent in an axial position to avoid A<1,3) strain, which would be present in alternative conformations. 

The relative stereochemistry of hyperaspine 93 was determined by 2-D NMR spectroscopic and mass spectrometry (MS) methods. It has a m-fused bicyclic conformation 93a <2001TL4621>. The trans-fused one is disfavored by an axial pentyl group at C-8 and by a destabilizing dipole-dipole interaction between the N- and O-atoms, which does not exist in the alternative //.(-conformation. The geminal coupling constant of C( 1 )H2 in 93 (11.0 Hz), and that of its 6-hydroxy derivative (11.2 Hz), indicates that they exist preferentially in / //-conformations, whereas their 6-epimers adopt trans-conformations (9.3 and 8.4 Hz, respectively) <2005EJ01378>. Nuclear Overhauser enhancement spectroscopy (NOESY) studies also confirmed the stereochemistry of 93 by the marked nuclear Overhauser effect (NOE) correlation between H-3 and H-4a <20030L5063>. 

PrPSc has a predominantly fl-sheet conformation 797 In vitro conversion of PrPc to alternative conformations 798... 

It also should be remembered that a crystal structure represents an average over all the molecules in the crystal and the time course of data collection. When alternative conformations for a side chain or ligand have been included in the crystallographic structure, one must decide which conformation to use in a simulation. 

Kelly, J. W. (1998). The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. Curr. Opin. Struct. Biol. 8, 101-106. 

Figure 15.8 (a) Structure and (b) alternative conformations of cobalamine found in B12-dependent enzymes. The functional group R is deoxyadenosine in AdoCbl, methyl in MeCbl and -CN in vitamin B12. (From Bannerjee and Ragsdale, 2003. Reprinted with permission from Annual Reviews.)... 

In contrast to the well-ordered but nonrepetitive coil structures, there are also genuinely disordered regions in proteins, which are either entirely absent on electron density maps or which appear with a much lower and more spread out density than the rest of the protein. The disorder could either be caused by actual motion, on a time scale of anything shorter than about a day, or it could be caused by having multiple alternative conformations taken up by the different mole-... 

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