Buildup procedure

Gilson, K. D. and Scheraga, H. A. (1987). Revised algorithms for the buildup procedure for predicting protein conformations by energy minimization. J. Comp. Chem., 8, 826-834. 

The majority of the sequential buildup procedures use energy-based methods for fragment scoring, although several of the methods use a rule-based approach. 

The site point connection approaches listed in category 2 may be viewed, in principle, as fragment-by-fragment sequential buildup procedures. However, an important difference is that the sequential buildup methods often allow for some conformational adjustment as eadi fragment is added to the ligand. This is not generally done with site point methods. 

There are several advantages to sequential buildup procedures. First, because each fragment is selected based on its ability to contribute to receptor binding, the ligands suggested by these methods should in principle be smaller and more efficient than molecules derived from fragment connection methods. Second, because each piece is added sequentially, it is possible to perform more detailed conformational analyses, leading to fewer misses. ... 

The connection/disconnection methods contain some features ot the sequential buildup procedures, as well as clever ways for altering bond connectivity of the ligand(s) during construction. Several of these techniques also sample the allowed conformational space of the fragments from which ligands are constructed. 

Figure 14 Representative ligand buildup procedure in GenStar. Reproduced with permission. See Ref. 118.

Moon and Howe described GROW, which uses a buildup procedure to determine the best peptidal ligand or substrate for a given enzyme. 

Methods using genetic algorithms or Monte Carlo methodologies are similar in some respects to atom buildup procedures in that there is no inherent restriction on the diversity available to the programs. Specialized constraints are required, however, to deal with problems of synthetic accessibility and to restrict the solution space searched by the algorithms. 

As an illustration of the first point, atom-based methods sometimes attempt to limit the number of possibilities to be searched by assuming only sp connections. Fragment buildup procedures can also lose diversity depending on how the fragments are permitted to join together (e.g., in the construction of... 

Constraints are typically applied as a penalty function that is added as an extra term in the scoring function, often as some simple function (e.g., harmonic) of the difference between the actual and target values. Other strategies are possible, however, and constraints have also been used systematically in the construction of model structures. This can be applied to distance constraints, where a buildup procedure is used to generate stmctures that satisfy all constraints [64]. Angle constraints can also be used to systematically search the conformational space, both using a branch-and-bound procedure [65] or in a tree-search algorithm in combination with distance constraints [66]. 

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