Ring systems conformational searching

Conformation analysis methods. In many cases in the process of building a 3D structure from scratch, decisions have to be made between multiple alternatives with similar energy. A typical example is an sp -sp torsion angle with similar energies for the alternatives of -i-60°, -60° and 180°. In many cases, rules are used to decide (e.g. stretch an open chain portion as much as possible to avoid clashes). Sometimes, the best result cannot be determined without a conformation analysis (e.g. complex ring systems with exocycHc substituents). Despite conformation analysis being a topic of its own covered in the next chapter, many automatic 3D structure generators have to fall back in certain situations to a limited conformation search in order so solve a specific problem and to come up with a reasonable solution. 

Now that structures could be optimized, some questions arose concerning the conformer searches. In version 3.1 of the SPARTAN software package, the conformer searching algorithm employed the method of Osawa for rings. While it is quite clear from theory how the search should proceed when applied to a monocyclic system, the implementation for bicyclic systems in unclear. 

Cyclizing open structures or creating an additional ring system in a given structure represents one of the useful methods in the search for biologically active conformations. The end result is a more constraint molecule, with an imposed conformation. This strategy is related to the conjunctive approach developed further on in this chapter. 

Bach year usually sees the publication of a handful of new methods for exploring conformational space. Many can be considered as variants on one of the approaches discussed thus far but which may provide some advantage in terms of the efficiency and effectiveness with which they explore conformational space. Some of these alternative methods are designed for quite specific types of molecule (such as ring systems) and as may not be particularly general approaches to conformational analysis. Here we describe in more detail two of these newer methods, one which extends the systematic search and one which uses an alternative approach to generating the initial structure prior to energy minimisation. 

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