Conformational predictions

RJ Petrella, T Lazardis, M Karplus. Protein sidecham conformer prediction A test of the energy function. Folding Des 3 353-377, 1998. 

Fasman, G.D. Protein conformational prediction. Trends Biochem. Sci. 14 295-299, 1989. 

Fig. 2.—Conformations of oligosaccharides having the angles shown in Table IX for minimum-energy conformations predicted by the HSEA algorithm for use as building units in molecular modeling. The molecules are shown without the anomeric hydroxyl group.

The reasons for the different outcomes in these conformational predictions are not clear at this time, but are being investigated further. Hydrogen bond energies were excluded in all predictions, thus strong attractive forces were not a factor in the observed differences. 

The anomeric effect dominates the conformational preference, but quantitative conformational predictions by presently described methods, based on additive treatments of steric effects taken in conjunction with the anomeric effect, do not accord with the observed data. 

The ramifications of the different conformational natures of 166-176 and other similar analogues on biological activity may be a promising area of future exploration. As a preliminary approach, a comparison of the low-energy conformers predicted by molecular mechanics and two-dimensional NMR data are under analysis. A possible correlation with conformational families of these flexible analogues and the antimalarial activity is under examination. 

For much more flexible molecules than 18, DFT PES scans can be impractical. Currently, for such molecules conformational analysis is most efficiently carried out in two stages first, Monte Carlo searching using a molecular mechanics force field (MMFF) determines the stable conformations predicted by the MMFF second, these conformations are re-optimized using DFT. For example, conformational analysis of the... 

A lanthanide-induced shift analysis of tetrahydrothiopyran 1-oxide based on calculated geometrical parameters indicated that the equilibrium mixture contained ca. 45% of the equatorial conformer in CDCI3 solution. However, the conformational equilibrium is solvent dependent, with the equatorial conformer predicted to be favored by polar solvents. The calculated dipole moments for the equatorial and axial conformers are 4.39 and 4.17 D respectively, which compare favorably with the experimental value of 4.19 D <1994J(P2)2329>. 

Molecular mechanics calculations and temperature-dependent CD spectra may reveal details of the conformational map not attainable by DNMR. Thus, double minima within each of the anti and syn forms were inferred from molecular mechanics calculations and were also supported by the temperature dependence of the CD spectra. Rotational strength calculations for the stable conformations predicted by the molecular mechanics calculations (or for any other arrangement) are in fair agreement with respect to both the sign and the dissymmetry factor for many of the studied compounds and may also allow for tentative assignments of absolute configuration in cases where this is not known (87JA492). 

Table 5.2. Summary of the loop conformational predictions results with the combination of standard and enhanced sampling procedures...

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...

The solid-phase 13C cross-polarization/magic angle spinning (CP/MAS) NMR, as a tool for conformation prediction, revealed that the solid-phase conformation of the nine-membered ring crown cavity in naphtho-9-crown-3 is different from benzo-9-crown-3. The two key C-0-CH2 units are predicted to be out of naphthalene plane, and the two C-C-O-CH2 torsion angle values are close to each other <2000JST(526)185>. 

Recent EHT calculations on the neostigmine molecule have led to a conformation prediction locating the onium group about 4.5 A from the carbonyl oxygen (81) in support of the postulated nicotinic pharmacophore (17). 

Molecular orbital calculations led to the prediction that two distinctly different conformations of equal preference prevailed for histamine (Figure 10) (25). The conformation of Figure 10 (bottom) was predicted to exist without any hydrogen bonding between an onium hydrogen and the ring nitrogen atom. Recent NMR analysis of an aqueous solution of histamine revealed that the two conformers predicted from EHT—MO do in fact... 

The lowest energy TS, which leads to the major product, has just the conformation predicted by EeUdn. The lowest energy TS leading to the minor product is also that predicted by Eelkin. In other words, Felkin s assumption of placing the largest... 

Fasman, G.D. (1990). Protein conformational prediction. In Proteins Form and Function. R.A.Bradshaw and M.Purton, eds. (Cambridge Elsevier Trends loumals), pp. 135 145. 

Steven M. Muskal s program for neural network simulator for protein conformation prediction and other data analysis. PCs under DOS. 

Mimicking the secondary structure of peptides has become one of the most important tools for rational drug design (44-47). These methods induce the synthetic analog to adopt a set of target conformations, which are designed to mimic the bioactive conformation predicted in the native substrate from biophysical techniques. Molecular surrogates... 

This mesomeric picture gives an intuitive explanation of the higher s character of the C-H equatorial bond, as it indicates a measure of sp2 hybridization in this case. One should then be tempted to draw a mesomeric picture showing similar delocalization in axial C 1—H and 05—H bonds, and moreover to extend such representations to ordinary ethers. However calculations for methanol and dimethyl ether in the staggered conformation predict that the effect should be much smaller for these compounds. In this respect, we may mention that the practical significance of the interaction of the oxygen p-type lone pair with the antiperiplanar OH bond in methanol has been recently questioned (20). So the effect discussed in this section may be restricted to the pyranose-like, acetal or mixed acetal type of compounds. 

A. Almond, A. Brass, and J. K. Sheehan, Dynamic exchange between stabilized conformations predicted for hyaluronan tetrasaccharides Comparison of molecular dynamics simulations with available NMR data, Glycobiology, 8 (1998) 973-980. 

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