Conformational data

Conformational data of this type can be obtained by solid-state C NMR spectrometry. The chemical shifts (peak positions) of the carbons on either side of any glycosidic linkage are sensitive to the conformation of the linkage. 

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... 

The third current approach is synthesis of peptide chains as models for the helical peptaibol (Section 8.2) and gramicidin (Section 8.3) ion channels. Considerable work has been carried out in the former area, involving synthesis of Aib-containing small peptides, in order to obtain conformational data applicable to the more complex oligopeptide antibiotics. By working with such fragments it has been possible to obtain valuable X-ray crystal structure information on the helical conformation of ala-methin 246), emerimicin 247), suzukacillin 248), and other members of the peptaibol series. 

McAllister, M. A., A. Perczel, P. Csaszar, and I. G. Csizmadia. 1993a. Peptide Models 5. Topological Features of Molecular Mechanics and Ab Initio 4D-Ramachandran Maps. Conformational Data for Ac-L-Ala-L-Ala-NHMe and For-L-Ala-L-Ala-NH2. J. Mol. Struct. (Theochem) 288,181-198. 

McAllister, M. A., Perczel, P. Csaszar, W. Viviani, J.-L. Rivail, and I. G. Csizmadia. 1993b. Peptide Models 4. Topological Features of Molecular Mechanics and Ab Initio 2D-Ramachandran Maps. Conformational Data for For-Gly-NH2, For-L-Ala-NH2, Ac-l-Ala-NHMe and For-L-Val-NH2. J. Mol. Struct. (Theochem) 288, 161-179. Mehrotra, P. K., M. Mezei, and D. L. Beveridge. 1984. Monte Carlo Determination of the Internal Energies of Hydration for the Ala Dipeptide in the C7, C5, aR, and Pn Conformations. Int. J. Quantum Chem. Quantum Biol. Symp. 11, 301-308. 

In six-membered cyclic nitronates (e.g., in (85)) adopting a half-chair conformation, the C-6 and C-5 atoms deviate from the plane of four atoms in the opposite directions, the deviation of the C-6 atom being substantially larger (the deviation of the C-5 atom. The latter is generally at most 0.05 A). It should be noted that one six-membered cyclic nitronate adopts a half-boat conformation (data from the Cambridge Structural Database, see also Fig. 3.2 and its discussion). 

The principle source of experimental conformational data in an NMR structure determination is constraints on short interatomic distances between hydrogen atoms obtained from NMR measurements of the nuclear Overhauser effect (NOE). NOEs result from cross-relaxation mediated by the dipole-dipole interaction between spatially proximate nu-... 

In de novo three-dimensional structure determinations of proteins in solution by NMR spectroscopy, the key conformational data are upper distance limits derived from nuclear Overhauser effects (NOEs) [11, 14]. In order to extract distance constraints from a NOESY spectrum, its cross peaks have to be assigned, i.e. the pairs of hydrogen atoms that give rise to cross peaks have to be identified. The basis for the NOESY assignment... 

Once the qualification protocols are complete, a qualification report is written. The qualification report should summarize the results from each of the protocols, explain any deviations or non-conforming data, and declare that the instrument is suitable for use (or unsuitable if the acceptance criteria were not met or the non-conforming data could not be justified). 

Proper treatment of dipole moments (or other properties) in flexible molecules thus involves evaluating Boltzmann populations (see discussion in Chapter 14). This is beyond our present scope and coverage will be limited to assessing the performance of different models with regard to their ability to reproduce the change in dipole moment with change in conformer. Data are presented in Table 10-7, with the usual series of theoretical models surveyed. 

Molecules in the gas phase provide an electron diffraction pattern which can be analyzed in order to obtain relative interatomic distances in molecules. Some of the distances depend on molecular conformation and, in principle, it is possible to extract conformational data (conformer structure and population). Rough estimates of energy barriers may also be obtained from the peak widths by comparing calculated and experimental distribution functions. Uncertainties on populations are rather high ( 10-15%). 

The unproven, but reasonable, assumption implicit to SAR-directed conformational studies, both experimental and theoretical, is that one of the stable intramolecular conformers is the "active conformation, A difficulty to applying conformational data in quantitative drug design is selection of conformational features for QSAR development. Moreover, molecular shape properties are preferable features to have available in design studies. Conformation is a component of shape. The properties of the atoms, most notably their "sizes," comprise an additional set of factors needed to specify molecular shape. 

Molecular orbital theory provides electronic, as well as conformational, data for inclusion in QSAR development. 

Until recently it was not customary to report measurements such as torsion angles and intramolecular non-bonding distances because they are not necessarily characteristic molecular properties. The bond torsion angles, which are of special interest in conformational analysis, are often only reported and discussed when there is a special reason for doing so which is connected with the objectives of the structure determination. Tradition dies hard, and one still finds tables of bond distances and angles in crystal structure papers which are not significantly different from the expected values, whereas torsion angles and other conformational data which are of special interest to the chemist are not reported and have... 

These three questions will be examined in relation to the conformational data which have been given by recent carbohydrate crystal structure determinations. Because of the added reliability and accuracy arising from the use of automatic diffractometers only those numerical data will be quoted where these instruments were used. 

The octasaceharide which carries an additional A -acetylglucosamine at the reducing end in comparison to the heptasaccharide was prepared by an independent synthesis. This compound shows a different conformational behavior than the heptasaccharide [122]. The minimum energy conformation, as calculated by the GESA program, shows the trisaccharide at the 6-position of the P-mannose bent back towards the reducing end. This particular effect is in qualitative agreement with the observation of the conformational difference between the tri- and the pentasaccharide described above. The NMR analysis of this octasaceharide confirms the calculated structure. One important fact for the correct prediction of the conformational data was the simultaneous treatment of all independent parameters in the optimization procedure (Table 8). 

Use of generalized coordinates, in which accurately known structural information such as certain bond angles and bond lengths and conformation data can be introduced as known parameters, decreases the number of unknown parameters so that the least squares fitting problem is tractable. Some skill is... 

Conformational Data for Germanium Alcohol 125 and Derived Esters 126a-h... 

NMR spectra of the combined flows as a function of the time following mixing using a pCoil NMR probe. This approach allows the acquisition of time-dependent protein conformational data that would be difficult to acquire by other means. While limited to the acquisition of 11 spectral data for obvious reasons, the method still has interesting potential. 

Tollenaere et al.n0l) have emphasized that as conformational data based on computer technology accumulates, a strong need is felt to visualize the results of the analyses and to be able to manipulate structures in a more sophisticated way than is possible by use of conventional molecular models. Models of the ball and stick and space-filling kind are cumbersome, easily transformed, and do not lend themselves to superposition one upon the other. These problems may be solved by the use of computer graphics, and evidence of the application of this facility is increasingly apparent in the opioid field. 

The present chapter briefly examines and discusses the effects of some additives, namely lyoprotectants (sugars, crown ethers, and methoxypoly(ethylene glycol)), on the activity and enantioselectivity of several lipases. A possible rationale for the increment usually observed when using lyoprotectants, on the basis of conformational data obtained by means of Fourier-transform infrared (FT-IR) spectroscopy is also suggested. 

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