Random methods conformational searching

Saunders 26 introduced a method that performs random molecular conformational searches in Cartesian rather than internal space. In this method, one starts with an initial conformation. Every atom in the molecule is given a... 

In a systematic search there is a defined endpoint to the procedure, which is reached whe all possible combinations of bond rotations have been considered. In a random search, ther is no natural endpoint one can never be absolutely sure that all of the minimum energ conformations have been found. The usual strategy is to generate conformations until n new structures can be obtained. This usually requires each structure to be generate many times and so the random methods inevitably explore each region of the conformc tional space a large number of times. 

Dmparison of various methods for searching conformational space has been performed cycloheptadecane (C17H34) [Saunders et al. 1990]. The methods compared were the ematic search, random search (both Cartesian and torsional), distance geometry and ecular dynamics. The number of unique minimum energy conformations found with 1 method within 3 kcal/mol of the global minimum after 30 days of computer processing e determined (the study was performed in 1990 on what would now be considered a / slow computer). The results are shown in Table 9.1. 

The most serious problem with MM as a method to predict molecular structure is convergence to a false, rather than the global minimum in the Born-Oppenheimer surface. The mathematical problem is essentially still unsolved, but several conformational searching methods for approaching the global minimum, and based on either systematic or random searches have been developed. These searches work well for small to medium-sized molecules. The most popular of these techniques that simulates excitation to surmount potential barriers, has become known as Molecular Dynamics [112]. 

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. 

Conformational isomers represent minima on an energy surface, and all structures and the corresponding strain energies can be obtained by a careful analysis. This can be performed manually (such as in Sections 17.3 and 17.4) or automatically. An automatic procedure may involve a systematic search (grid search methods), a stochastic search (e.g., torsional Monte Carlo or cartesian stochastic, i.e., the random kick method) or molecular dynamics (see Chapter 5 and Section 16.5). Implemented in MOMEC is a random kick stochastic search module, and this has been shown to lead to excellent results, not only for conformational equilibria, but also for distributions of configurational isomers[37]. 

In general, five different approaches can be distinguished and are applied to explore the conformational space of a molecule systematic searches, rule-based and data-based approaches (model building), random methods, genetic algorithms, distance geometry, and simulation methods. Some of the basic principles and ideas behind these concepts have already been described in the Secs. 2 and 3 of this article. In the following, the application of these concepts to conformational analysis and searches will be discussed. 

Stop criterion. In contrast to systematic searches that can stop if all possible combinations of different torsion angles have been enumerated, random methods do not have a natural endpoint. In most cases, the search is stopped if no new conformations are found (i.e., if several conformations have been generated several times). 

Two procedures based on random search have been reported for predicting loop conformations for use in homology modeling. Shenkin, Yarmush, Fine, Wang, and Levinthal s random tweak method is designed to address the problem that a randomly generated conformation may fail to satisfy the imposed... 

Molecular model-building (conformational search) methods fall into two general classes systematic and random. - Systematic methods search all possible combinations of torsional angles, whereas random methods usually involve a Monte Carlo (with Metropolis sampling ) or molecular dynamics trajectory. Both approaches attempt to search large areas of conformational space and eventually converge on the desired conformation or structure. Dis-... 

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