Conformationally flexible molecules

Currently there is only one product that adopts this approach and this is NMRPredict from Modgraph. It is based on the work by Prof. Ray Abraham at the University of Liverpool (UK). This approach calculates chemical shifts for a range of low energy conformers and averages them to give a net chemical shift. This approach seems to offer the most accurate prediction of chemical shift but the disadvantage is that it is very slow (particularly for conformationally flexible molecules). 

Ouvrard, C., Price, S.L., 2004, Toward Crystal Structure Prediction for Conformationally Flexible Molecules The Headaches Illustrated by Asprin, Crystal Growth and Design, Vol.4, No. 6, 1119-1127. 

Conformation dictates overall molecular size and shape, and influences molecular properties as well as chemical reactivity. Experimental information about conformation is often scarce, and computational methods may need to stand on their own. There are actually two different problems associated with treatment of conformationally-flexible molecules. The first is to identify the appropriate conformer (or conformers), and the second is to locate it (them). Both of these will be touched on in turn. 

At a more detailed level, we note that the solvent effects on the optical rotation have the same origins as solvent effects on the energy itself, as described in detail in other contributions to this book. Most other studies of solvent effects on natural optical activity have focused on the electrostatic contributions. These contributions can be partitioned into direct effects arising from the influence of the dielectric environment on the electronic density of the solute, and into indirect effects arising from the relaxation of the nuclear structure in the solvent. For conformationally flexible molecules, we may also consider a third possible solvent effect due to the changes in the conformational equilibria when going from the gas phase to solution. 

With the exception of sterols most membrane lipids are conformationally flexible molecules. The question arises whether the concept of conformational restriction can be extended from peptides to the field of sphingolipids. The observation that conformationally restricted derivatives of myristic acid have selective toxicity towards trypanosomes demonstrates that this strategy is also applicable... 

Tam et al. [141] attempted to determine how reliable and accurate CC and DFT/ TDDFT calculations are for this conformationally flexible molecule. In addition, they explored the sensitivity of the chiroptical response to two different factors. One was the accuracy of the mole fractions, and another was how different were the ORs of individual rotamers calculated at different levels of theory. It was found that with DFT, at the B3LYP/aug-cc-pVDZ level, the optical rotations were overestimated while CC yielded better agreement with experiment [141, 142], The predicted gas phase optical rotation, averaged by CC or DFT mole fractions, were not in good agreement with either gas or solution phase experimental measurements. The DFT calculated optical rotations differed between 15 and 65% from experiment. 

The experiments with N2 cryostats are usually run at temperatmes between 100 and 170K the desire for the lowest possible temperatme is balanced by the necessity to avoid icing. Such temperatmes are almost always sufficient to prevent both the chemical (or photochemical) decomposition of the sample and the solvent loss. The choice between rapid (flash) and slow cooling depends on the natme of the sample. When the thermal expansion coefficient is likely to be high, as is usually the case with conformationally flexible molecules, slow cooling is preferable if the crystal stability permits it. On the other hand, flash-cooling is the only technique possible for protein crystals, because slow cooling will allow the crystallization water to form ice crystals,... 

Clark, D.E., Willett, P. and Kenny, P. (1992). Pharmacophoric Pattern Matching in Files of Three-Dimensional Chemical Structures Use of Smoothed-Bounded Distance Matrices for the Representation and Searching of Conformationally-Flexible Molecules. J.MoLGraphics, 10,194-204. 

Demeter, D.A., Weintraub, H.J.R. and Knittel, J.J. (1998). The Local Minima Method (LMM) of Pharmacophore Determination A Protocol for Predicting the Bioactive Conformation of Small, Conformationally Flexible Molecules. J.Chem.lnf.Comput.Sci.,38,1125-1136. 

Nicklaus, M.C., Milne, G.W.A. and Burke, T.R. (1992). QSAR of Conformationally Flexible Molecules Comparative Molecular Field Analysis of Protein-Tyrosine Kinase Inhibitors. J.Comput.Aid.Molec.Des., 6,487-504. 

It has been shown by Tute and collaborators (228) that the theoretical evaluation of logP on the basis of additivity principles can lead to misleading results for certain molecules (e.g., heterocyclics, sterically crowded or conformationally flexible molecules). This difficulty has been recently rationalized for rigid structures (229) Experimentally measured logP values are therefore more reliable than those estimated from component it values ... 

The directionality property of the parameters is most relevant to conformationally flexible molecules and to the description of differences in reactivity of optical isomers. The steric substituent constant reflects the weighted average of the steric effects in variously populated conformations that contribute to the observed property. For example, an indication of different steric effects in conformationally locked compounds can be obtained from the hydrolysis of methyl trans- and cis-4-t-butyl cyclohexane-carboxylates (100) ... 

The growing interest in unravelling the mechanism of action of dopamine and related compounds at the molecular level started with the considerations of the conformation(s) of the dopamine molecule when bound to the receptor site. Dopamine itself is a conformationally flexible molecule that can adopt specific conformation(s) needed to achieve appropriate three dimensional interaction with various groups located at or near the recognition (receptor) site(s). 

Lambert MH. Docking conformationally flexible molecules into protein binding sites. In Practical application of computer-aided drug design. New York Dekker, 1997. p. 243-303. 

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