Conformations 7 Three-dimensional Structure Generation

These 3D models describe a fixed conformation. The only permissible motions of this model are 3D translations and rotations of the molecule as a whole. The relative mobility of parts of an individual molecule can also be described on the basis of its 3D coordinates (see Three-dimensional Structure Generation Automation). It requires the specification of so-called rotatable bonds to record permissible or feasible changes of the conformation. Conformational analysis programs use such a model as their internal problem representation. Partially flexible ring systems require additional sophistication to be modeled adequately using this approach. 

As outlined in other chapters in this volume, Tomalia et al. first reported the successful well-characterized synthesis of dendrimers in the early 1980s [1], These molecules range in size from 10 A to 130 A in diameter for generation 0 (GO) through generation 10 (G10). In the ideal situation, PAMAM dendrimers are monodispersed spherical conformation with a highly branched three-dimensional structure (Figure 18.1) that provides a scaffold for the attachment of... 

When the three-dimensional structure of the target receptor is known, receptor-based techniques can be applied to combinatorial library design. We adapted the combiBUILD program from the original BUILDER program to generate and evaluate these virtual combinatorial libraries. It was developed for the case where the orientation of the scaffold in the active site is known, and therefore focuses on examining the conformations of the... 

The basic starting steps are the generation of three-dimensional structures, conformation search and compound alignment with respect to a compound itself or a -> pharmacophore. 

The first step of the CoMFA approach consists in the selection of a group of compounds having a common —> pharmacophore, in the generation of three-dimensional structures of reasonable conformation and in their alignment. 

Molecular docking and structural alignment methods are based on three-dimensional structures of candidate molecules that can be generated by rule-based methods such as CORINA [13, 14] or CONCORD [15]. However, methods based on three-dimensional structures are computationally quite demanding and cannot routinely be applied to databases of hundreds of thousands of compounds today. For this reason, a number of fast methods to determine molecular similarity have been developed that operate solely on connectivity and atom types of molecules. Such tools allow rapid prescreening of very large databases and avoid a conformational analysis of each candidate molecule. 

For peptides and nucleic acids, the system should provide rapid generation of a model from sequence data in any of the commonly observed conformations (e.g., a-helix, /J-sheet, /2-turn, B-DNA, Z-DNA). For peptides, it should be possible to make insertions or deletions in the sequence easily and to mutate side chains for homology model-building applications, where the sequence of the unknown structure is mapped onto the three-dimensional structure of a sequentially homologous protein whose structure has previously been determined by X-ray crystallography. 

In this chapter, we have emphasized that protein function Is dependent on protein structure. Thus, to figure out how a protein works, Its three-dimensional structure must be known. Determining a protein s conformation requires sophisticated physical methods and complex analyses of the experimental data. We briefly describe three methods used to generate three-dimensional models of proteins. 

The three-dimensional structure of folylpolyglutamate synthase of Lactobacillus casei and E. coli have been determined by X-ray crystallography. The catalytically active conformation of the protein is obtained by bonding of a folate-type substrate binding of ATP is not, perse, sufficient to generate that conformational state. 

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