X-ray conformation

Nonnal mode analysis was first applied to proteins in the early 1980s [1-3]. Much of the literature on normal mode analysis of biological molecules concerns the prediction of functionally relevant motions. In these studies it is always assumed that the soft normal modes, i.e., those with the lowest frequencies and largest fluctuations, are the ones that are functionally relevant. The ultimate justification for this assumption must come from comparisons to experimental data. Several studies have been made in which the predictions of a normal mode analysis have been compared to functional transitions derived from two X-ray conformers [4-7]. These smdies do indeed suggest that the low frequency normal modes are functionally relevant, but in no case has it been found that the lowest frequency normal mode corresponds exactly to a functional mode. Indeed, one would not expect this to be the case. 

A block Lanczos algorithm (where one starts with more than one vector) has been used to calculate the first 120 normal modes of citrate synthase [4]. In this calculation no apparent use was made of symmetry, but it appears that to save memory a short cutoff of 7.5 A was used to create a sparse matrix. The results suggested some overlap between the low frequency normal modes and functional modes detennined from the two X-ray conformers. 

The minimum energy conformation yg if it exists in A should be the X-ray conformation Because the ground state is given by the X-ray conformation, the calculated free energy of all non-X-ray conformations should be higher than that of y - In other words ... 

The extensive data generated from x-ray studies with HRV-14 permitted the development of a model that could define the properties required of this class of compounds for antiviral activity [37], This model was dependent on the orientation and x-ray conformational data for compounds bound to the viral pocket. Some assumptions were made based on earlier results and on rules generated for predicting compound orientation. For example, it... 

Fig. 12 shows that, within the CNDO approximation, the X-ray conformation is no longer adopted in solution. In fact, the complex oscillates around the S conformation (Fig. 13) from the gauche C to the symmetrical C conformation (Fig. 14). A close look at this motion indicates that it may be decomposed into a simultaneous...

Rotation around a linkage between two sugars may take place. This influences the shape of the disaccharide, and affects the conformation that the polysaccharide will adopt. When a carbohydrate polymer is obtained in crystalline form, characterization of its shape is possible by using X-ray diffraction. However, it is not at all certain that this X-ray conformation will be that of the active form in the biological environment. Nevertheless, it constitutes a basis for formulating hypotheses concerning the shape in a biological environment. 

Fig- 17 The X-ray structure and three conformational classes of discodermolide identified by NAMFIS analysis of the NMR spectra in DMSO-d6. a The X-ray conformation, b The corkscrew form, c The sickle motif, d An extended or awl form. (Reprinted with permission from [60]. Copyright 2001 American Chemical Society)... 

The similarity of its bioactive and X-ray conformations had been anticipated on the basis of SAR data and of its structural homology to dictyostatin [125], Dictyostatin (Fig. 16) is another MT-stabilizing agent that competes with PTX and has a similar effect on MT dynamics [125], The preferred solution structure of the conformation-ally constrained dictyostatin overlays quite closely the tubulin-bound conformation of DDM, suggesting that they interact in a similar way with MT (Fig. 19). This hypothesis was further supported by the synthesis of a macrocyclic DDM/dictyostatin hybrid, that displays considerable antiproliferative activity [126],... 

Fig. 23 Overlay of selected conformers of laulimalide within 2 kcal mol-1 of the global minimum determined from molecular modeling and NMR data in CD3OD solution. These low-energy conformations closely resemble the X-ray conformation. (Reprinted with permission from [134]. Copyright 2005 Elsevier)...

Fig. 5.2. Active site of the P450 BM-3/NPG complex in (a) the low temperature X-ray conformation (PDB ljpz) representative of distal state where the NPG (shown in green) is distant from the heme iron, with Phe87 (shown in magenta) interposed between NPG and heme iron (shown in blue) and (b) the alternative active site of the conformation predicted by Jovanovic et al. representative of the proximal state where Phe87 has changed its rotameric state to allow NPG to approach the heme iron...

Docking to multiple receptor conformations (sometimes abbreviated MRC [8]) can be applied on a set of conformations from any source. Experimentally different X-ray conformations or NMR solution stmctures can represent the same biomolecular system. NMR solution stmctures and conformations sampled during an MD simulation represent a valid thermodynamic ensemble, e.g., a canonical ensemble, for simulations with constant number of particles, volume, and temperature. Although, a collection of X-ray stmctures is not a valid thermodynamic ensemble, docking to multiple X-ray stmctures is sometimes also termed ensemble docking. 

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