Stabilization, of conformations

In the previous sections, we focused our attention upon nonbonded interactions and their effect upon the relative stability of conformational and geometric isomers. We shall now use OEMO theory in order to examine how geminal lone pair-lone pair, bond pair-lone pair and bond pair-bond pair interactions can affect the shape of a molecule264. ... 

The preferential stabilization of conformation [96] by the cation is annulled upon binding of the cation with a cryptand. Similar effects have been observed with crown ethers. The sodium salt of acac in methanol at —58°C consists of 35% [104] and 65% [105]. The addition of 18-crown-6 [3] shifts the... 

Solvent polarization can also play a role in the stabilization of conformationally nonuniform particles. For example, 4-(l-phenylpiperidin-4-ylidene) cyclohexylidene propanedinitrile transforms into completely charge-separated species on photoirradiation. This species contains the C=C bond and bears two ion-radical centers N and C. As explained (Floogesteger et al. 2000), the species formed keeps a folded conformation in cyclohexane and a stretched conformation in benzene. 

In the enkephalin studies we began to see how theoretical techniques can be used to generate conformations of related molecules. With the results from GnRH and vasopressin we saw how flexible these molecules are and how the conformational fluctuations and dynamics of these molecules can be studied. We also saw how the relative stabilities of conformations of a molecular fragment can be influenced by conformational constraints of the whole molecule. In the following section we will present some ideas on how these calculations can be incorporated into a conformational based approach to drug design. 

The semiempirical valence electron methods have been widely employed for calculating total energies as a function of the conformational degrees of freedom the relative stability of conformers and energy barriers are obtained in the different acyl heterocyclic derivatives. The degree of reliability of the different approaches varies, depending only on the molecular structure ... 

Let us mention that there are still other relations between conformation and dipole moments. Relative stability of conformational isomers was often brought in connection with their dipole moments. For instance, the preferred sp conformation of esters (3a), or of carboxylic acids, was often explained by the lower dipole moment6 compared to the conformation 3b, or in other words by the electrostatic repulsion7-9 of partial dipoles in 3b. Reasoning of this kind is usually based on anticipated rather than measured moments that of 3b cannot be directly measured. Interaction of more distant dipoles is commonly neglected, viz both its effect on the conformation and on the total /z (see, for example, Klinot and coworkers10). This is in fact the fundamental assumption underlying all analyses of dipole moments. 

In practice, it makes little difference whether one believes that the anomeric effect is destabilizing or stabilizing since one can arrive at the same conclusion concerning the relative stability of conformers or isomers. For instance, for a molecule which can take the two conformations 2 and... 

F. Y. Naumkin andF. R. W. McCourt,/. Chem. Phys., 107,1185,5702 (1997). A Study of the ArCl2 van der Waals Complex Ab Initio-Based Potential Energy Surfaces, the Relative Stability of Conformers, and the Hidden Microwave Spectrum. 

Determining the Relative Stabilities of Conformations of Cyclohexane Derivatives... 

Gas-phase NMR spectroscopy has been used to obtain equilibrium constants and rate constants for many low-energy molecular processes. These data have been used to address questions regarding the relative stability of conformers and tautomers in the gas phase, the kinetics of exchange processes in the gas phase, and the direction and magnitude of solvent effects on these equilibria and processes. Most of the studies have appeared in the last 10 years. Continued progress in NMR instrumentation and techniques as well as considerable recent developments in kinetic theory ensure that the next 10 years will see many novel applications of gas-phase NMR spectroscopy. 

So, multiple MD is a good tool to assess the stability of conformers short biomolecules (this was also seen for the related peptide Tyr-Thr-Gly-Pro [50]). Due to the long length of the equilibration phase of a biomolecular system in aqueous solution, multiple MD simulations cannot be used in a blind systematic manner on a large ensemble of conformations. But it is very informative on a selected set of conformers, which have been derived by knowledge based conformational searches. The limit of the multiple simulation size in explicit water is about 10 conformers. Database searches seen to be a very good tool to derive low energy conformers all the conformations found in the structural database were found to be at least 1% populated in the 33.6 ns of simulation. 

Short free MD simulations are a useful tool to check the stability of conformations, i.e. whether they are local minima. 

As the hydrogens of ethane are replaced by other atoms or groups of atoms, other factors affecting the relative stability of conformations appear van der Waals forces, dipole-dipole interactions, hydrogen bonding. But the tendency for the bond orbitals on adjacent carbons to be staggered remains, and any rotation away from the staggered conformation is accompanied by torsional strain. 

We might have made a different guess about the preferred direction of attack, and even a different estimate about relative stabilities of conformations, but we would still arrive at the same basic conclusion except by sheer coincidence, the two diastereomers would not be formed in equal amounts. 

Figure 2-16 Stabilization of conformations by secondary bonding forces.

It is not always necessary to detail the electronic behavior of materials an accurate understanding of the atomic interactions is often sufficient to describe the phenomenon of interest with reasonable accuracy. In contrast to ab initio methods, molecular mechanics is used to compute molecular properties, which do not depend on electronic effects. These include geometry, rotational barriers, vibrational spectra, heats of formation, and the relative stability of conformers. As the calculations are fast and efficient, molecular mechanics can be used to examine systems containing thousands of atoms. However, unlike ab initio methods, molecular mechanics relies on experimentally derived parameters so that calculations on new molecular structures may be misleading. 

The electrostatic concept predicts the stability of conformers in qualitative agreement with experimental observation, but quantitative accord cannot... 

---