Exhaustive Conformational Searching Methods

Another grouping of the various conformation search methods is based on the coordinate system in which they operate. For the potential advantages of the external (Cartesian) and internal (bond lengths, bond and torsional angles) systems, the reader is referred to Refs. 71 and 75. 

A different technique used for exploring conformational space is the molecular dynamics method. While it is effective for searching local conformational space, it requires remarkably more computer time than the other methods for global search problems.  

In the case of strained cyclic structures, the exhaustive generation of 3D isomers usually requires looser geometric constraints. Thus, some of the conformers obtained could be distorted with respect to the reference geometric parameters. In this case an original strain minimization techniqne (PMM) is applied based on a simple energylike fnnction, where the electrostatic terms are omitted. 

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Initially, these methods relied on the exhaustive conformational search algorithms of Dammkoehler et al. [33]. The most recent versions of this methodology, however, employ a Constrained Conformational Search [34], in which interesting regions of space are determined in an initial phase, and subject to more detailed conformational analysis in a later phase. 

A docking program basically consists of two parts a exhaustive, fast, and robust conformational search of the ligand, preferably exhaustive, fast, and robust, and a method of calculating and scoring the observed interactions, which, ideally, should be fast and accurate. 

Another way to simplify the tertiary structure problem is to fix the backbone and then carry out an exhaustive search on the allowed side chain conformations. Desmet and co-workers have developed a dead-end elimination method for searching side chain conformations. Side chain conformations are grouped into a limited set of allowed rotamers. While an exhaustive search of all possible combinations of these rotamers is still not feasible, the application of the dead-end elimination theorem allows removal of impossible combinations early in the search, thus controlling the combinatorial explosion and leading to a small group of possible final solutions. The possible solutions can then be compared to find the best possible structure. 

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