Selectivity systematic conformational search

The algorithm for the systematic conformation search starts with a minimized molecule. The rotatable bonds are selected along with the rotation increment and all possible conformations are created. At this point the search is terminated or each of the proposed conformations is energy minimized according to predefined parameters. After the database of conformers is finalized, each structure is compared to all the other structures through superimposition. Two... 

Perczel, A., O. Farkas, and I. G. Csizmadia. 1996. Peptide Models XVI. The Identification of Selected HCO-l-SER-NH2 Conformers via a Systematic Grid Search Using Ab Initio Potential Energy Surfaces. J. Comput. Chem. 17, 821-834. 

Two classical methods are available in THINK to perform the conformational expansion of molecules systematic search and random search. When the systematic search option is used, the use of contacts check avoids high-energy conformations and reduces the overall processing time. The random method uses a random number generator to select the conformations from within the estimated total number of conformations. The implementation of the program does not prohibit identical conformations to be output resulting from symmetry. These conformations are used in the pharmacophore generation and site search modules. 

The computational study of the osmium dihydroxylation of aliphatic al-kenes is much more complicated than the case of aromatic alkenes due to the large number of conformations that the former could adopt. To overcome this issue, we considered the system to be composed of two different parts the catalyst and the olefin. For the catalyst, the conformation considered is that from the X-ray structure. As already shown in the study of styrene [95], and in some experimental works [98], the catalyst is a fairly rigid molecule. For the aliphatic alkenes under study, there is a large number of possible conformations in addition, the stability of an olefin conformation is also affected by the interactions between the olefin substituent and the catalyst. Therefore, the catalyst must be included in the conformational search. The conformational analysis was done using a scheme based on the systematic search approach [99]. The strategy consisted of two parts first we developed a method to identify all of the possible conformations afterwards, we screened all of the possible conformations at MM level to select the most stable. Finally, we only carried out the relatively expensive QM/MM calculations on these selected conformations. 

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. 

In the case of a larger number of degrees of freedom, a non-systematic search is the only option. Today, the fastest approach available is to analyse the structural databases, because they naturally provide selections of the high-density regions of the conformational space. One can exploit the structural information in databases at two levels either to look for a specific structural... 

A particular advantage of the low-mode search is that it can be applied to both cyclic and acyclic molecules without any need for special ring closure treatments. As the low-mode search proceeds a series of conformations is generated which themselves can act as starting points for normal mode analysis and deformation. In a sense, the approach is a systematic one, bounded by the number of low-frequency modes that are selected. An extension of the technique involves searching random mixtures of the low-frequency eigenvectors using a Monte Carlo procedure. 

The selectivities were calculated using the Boltzmann distribution, based on the energies of the most stable conformations. The authors performed a conformational analysis for each of the 12 different pathways of approaching of the olefin to the osmium tetroxide. They combined two techniques, the pseudo-systematic Monte Carlo [65] to explore the entire conformational space, and the Low Mode [66] searching to explore exhaustively a local region of the potential energy surface (Table 2). 

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