Molecular Superposition

Three-dimensional superposition is an abstract task involving the placement of one object in the space of another. Computational techniques that superimpose molecules serve as a focal point for the interpretation and understanding of molecular data. Superposition plays an important role in correlating a wide assortment of information (e.g., energetic, physiochemical, biological, or pharmacokinetic), as all of these depend on 3D overlap of some physical characteristic. Energetics is dictated by a balance of nuclear and electronic forces; solvation and receptor recognition are dependent on the conformation and the discrete interactions a molecule makes with its surroundings. Each of these is directly dependent on a molecule’s spatial arrangement if atoms of similar characteristics are placed in the same location, they are expected to effect a similar result. The means by which molecular superposition is used to interpret this type of information varies almost as much as the data to be interpreted. For methods that describe data in terms of molecular characteristics, atoms, functional groups, or physical attributes, molecular superposition is the component common to all techniques. Techniques such as comparative molecular field analysis and 3D similarity are all founded on molecular superposition. Similarities may be used in compound design, compound optimization, and the identification of new compound classes. The resulting superposition sets are often generalized and the consistent spatial information referred to as a pharmacophore. The principal difficulty faced in molecular superposition is one of combinatorics. The number of ways even a pair of molecules may be superimposed is large, making the problem inherently complex. The problem becomes even more difficult when the conformational space of the molecules is considered. As a result, most successful techniques reduce the problem, either by directing the search through heuristics or by using sampling techniques. The scope of this discussion will be restricted to small drug-like molecules. An equally large literature exists for macromolecular systems, although the issues and applications are somewhat different. Superposition techniques may be broadly divided into two classes, those that are atom based, relating atoms or fragments of one molecule to those of another, and those that make use of molecular fields, volumes, or surfaces. Flexibility and conformation must be addressed with each of these techniques.