Handling Ring Systems

Side chain generation is often a source of error. It will be most reliable if certain rules of thumb are obeyed. Start with structurally conserved side chains and hold them fixed. Then look at the energy and entropy of rotamers for the remaining side chains. Conventional conformation search techniques are often used to place each side chain. 

Model optimization is a further refinement of the secondary and tertiary structure. At a minimum, a molecular mechanics energy minimization is done. Often, molecular dynamics or simulated annealing are used. These are frequently chosen to search the region of conformational space relatively close to the starting structure. For marginal cases, this step is very important and larger simulations should be run. 

Model verification provides a common-sense check of results. One quick check is to compare the minimized energy to that of similar proteins. It is also important to examine the structure to ensure that hydrophobic groups point inward and hydrophilic groups point outward. 

It is quite common to do the conformation search with a very fast method and to then optimize a collection of the lowest-energy conformers with a more accurate method. In some cases, single geometry calculations with more accurate methods are also performed. Solvent effects may also be important as discussed in Chapter 24. 

The simplest and most quickly computed models are those based solely on steric hindrance. Unfortunately, these are often too inaccurate to be trusted. Molecular mechanics methods are often the method of choice due to the large amount of computation time necessary. Semiempirical methods are sometimes used when molecular mechanics does not properly represent the molecule. Ah initio methods are only viable for the very smallest molecules. These are discussed in more detail in the applicable chapters and the sources mentioned in the bibliography. 

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The number of possible conformations rises dramatically with increasing ring size. Therefore, large ring systems carmot be handled by the methods applied to small rings. However, in rigid polymacrocyclic structures for example, an overall... 

Ansamycins are a class of macrocyclic compounds in which non-adjacent positions on an aromatic ring system are spanned by the long aliphatic bridge (Latin ansa = handle). The aromatic portion may be a substituted naphthalene or naphthaquinone, or alternatively a substituted benzene ring. The macrocycle in the ansamycins is closed by an amide rather than an ester linkage, i.e. ansamycins are lactams. The only ansamycins currently used therapeutically are semi-synthetic naphthalene-based macrocycles produced from rifamycin B. 

All cubanes are high energy materials and should be handled with due precautions for potential explosives [ 1]. The ring system has almost 700 kJ/mol strain energy (more, per unit weight, than the detonation energy of TNT) and is under study as a basis for high power explosives [2,3]. Cubane itself explodes spontaneously at 3 GPa pressure, the... 

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