Structure generation methods

Once a molecular geometry, or ensemble of conformers, has been produced, the central computational step involved in CSP is the generation of trial crystal structures (Fig. 5.1). The goal of crystal structure generation methods is to produce aU possible, physically reasonable arrangements of molecules in a translationaUy repeating arrangement. 

The success of crystal structure generation methods for rigid molecules has been quite high across the blind tests, with most of the participants locating the observed structure somewhere in their lists for most molecules in categories 1 and 2. The notable exceptions are molecules XI, IX, and xm (Table 1). 

These blind test results have not only identified some important limitations of the search methods that are in use for CSP but have also highlighted some methods that have been found to be reliable across the series of tests. The third and fourth blind tests highlighted structure generation methods based on simulated annealing and random or quasi-random sampling as being most consistently successful." ... 

Structure generation methods can be broadly divided into two categories those which follow a deterministic course and those which are stochastic in nature,... 

This section describes briefly some of the basic concepts and methods of automatic 3D model builders. However, interested readers are referred to Chapter II, Section 7.1 in the Handbook, where a more detailed description of the approaches to automatic 3D structure generation and the developed program systems is given. 

A descriptor for the 3D arrangement of atoms in a molceulc can be derived in a similar manner. The Cartesian coordinates of the atoms in a molecule can be calculated by semi-empirical quantum mechanical or molecular mechanics (force field) methods, For larger data sets, fast 3D structure generators are available that combine data- and rule-driven methods to calculate Cartesian coordinates from the connection table of a molecule (e.g., CORINA [10]). 

M and A R Leach 1994. Current Methods for Site-Directed Structure Generation. Journal of nputer-Aided Molecular Design 8 467-475. 

Structure Generation, QSAR, and GoMFA Modeling Methods. 

Here, an attempt to classify different strategies to generate 3D molecular models is undertaken with the aim to specify the remit of methods which will be covered under the term automatic 3D structure generators . The focus will be on methods designed for small, dmg-like molecules. The prediction of the geometry of polymers, in parhcular of biopolymers, is a task of its own and not even attempted by the approaches discussed here. 

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. 

As it was mentioned in Section 9.4.1, 3D structures generated by DG have to be optimized. For this purpose, MD is a well-suited tool. In addition, MD structure calculations can also be performed if no coarse structural model exists. In both cases, pairwise atom distances obtained from NMR measurements are directly used in the MD computations in order to restrain the degrees of motional freedom of defined atoms (rMD Section 9.4.2.4). To make sure that a calculated molecular conformation is rehable, the time-averaged 3D structure must be stable in a free MD run (fMD Sechon 9.4.2.5J where the distance restraints are removed and the molecule is surrounded by expMcit solvent which was also used in the NMR measurement Before both procedures are described in detail the general preparation of an MD run (Section 9.4.2.1), simulations in vacuo (Section 9.4.2.2) and the handling of distance restraints in a MD calculation (Section 9.4.2.3) are treated. Finally, a short overview of the SA technique as a special M D method is given in Sechon 9.4.2.6. 

Fiser A, Sali A. 2003. Modeller generation and refinement of homology-based protein structure models. Methods Enzymol 374 461-491. 

Pearlman, R.S. (1993) 3D molecular structures generation and use in 3D searching, in 3D QSAR in Drug Design. Theory Methods and Applications, 1st edn (ed. H. Kubinyi), FSCOM Science Publishers, Leiden, pp. 41—79. 

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