Because one often needs to include unusual inhibitors or cofactors in the refinement, it is very desirable that the definition of geometry should be general. Often the structures of these small molecules have not been determined and their `ideal' geometry must be constructed from the fragments whose structures are known. In the present package, standard geometry is defined by breaking the structural model into components, such as amino acids, nucleotides or cofactors. The geometry restrains are then defined in a general way for each component and for the linkages between components.
There are two ways in which stereochemical information can be incorporated into the refinement process; the information can be added as additional observations (restraints) (cf. Hermans & McQueen, 1974; Konnert & Hendrickson, 1980) or the model can be parameterized (constrained) in such a way that the stereochemistry is always `ideal' (cf. Diamond, 1971; Warme, Go & Scheraga, 1972). Although the use of constraints rather than restraints does result in a more favorable ratio of observations or parameters, we have chose the latter approach. There are several reasons for this, the first being that a restrained model is physically more realistic than a constrained one, as constraints are usually implemented (e.g. Ten Eyck, Weaver & Matthews, 1976). A second reason is that different types of restraint can be individually weighted. This allows the user to put a smaller weight on geometric restraints for which the `ideal' values are uncertain. Another reason is that the significance of deviations from ideality can be evaluated by calculating the standard deviation of all the observations within the same class of restraint. At the same time the library of standard values can be tested for accuracy. If there is an error, then there will be a systematic difference between the library value and the value obtained from the refined model. (The `stereochemistry' program in the refinement package will perform both the above tests.) Finally, the use of restraints allows the stereochemical information to be incorporated into the refinement in a manner formally similar to the incorporation of the crystallographic observations (see below). This allows simpler and more efficient code.