Conformational energy surfaces, testing

In practice, one usually defines a training set of molecules and associated experimental properties and fits the relevant data with an assumed force field.The next step is to test the results on molecules and data outside the training set. Experimental data that depend on the energy surface and that may be used to determine the parameters of the intramolecular interactions consist mainly of gas-phase structural data derived from microwave spectra or electron diffraction patterns, crystal structures derived from X-ray and inelastic neutron scattering measurements, and vibrational frequencies obtained from infrared and Raman spectra. Torsional barriers are derived from NMR band shapes and relaxation times, whereas conformational energies are determined from spectroscopic and thermochemical data. Nonbonded parameters are determined mainly from... 

The examples discussed in Section 14.3 show how geometry optimization tools, combined with statistical rate theory, can be employed to access experimental timescales corresponding to folding, conformational changes associated with function, and amyloid formation. Most of the computer time used in such calculations is spent on finding transition states on the potential energy surface. These algorithms have been tested quite extensively, and it does not seem likely that much improvement will be possible beyond the DNEB/hybrid EF approach described in Section 14.2.1, or related schemes. 

In addition, the results of absorption studies for a series of (i-adrenoceptor blockers in vitro using Caco-2 monolayers and rat intestinal segments have been used to test new descriptors [55]. For this purpose, the authors calculated dynamic molecular surface properties considering all low-energy conformations. Molecular mechanics were used to consider the flexibility of the molecules, and the van der Waals volume (vdW) and water-accessible surface areas were also calculated (Table 4.18 and 4.19). When the dynamic polar vdW surface areas were used in regression analysis to describe cell permeability data obtained in Caco-2 cells and in rat ileum, excellent correlations were obtained (r2 = 0.99 and 0.92 respectively). 

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