Conformation search

Figure 4.49 reprinted with permission from Pranata J and W L Jorgensen. Computational Studies on FK506 Conformational Search and Molecular Dynamics Simulations in Water. The Journal of the American Chemical Society 113 9483-9493. 1991 American Chemical Society. 

The input to a minimisation program consists of a set of initial coordinates for the system. The initial coordinates may come from a variety of sources. They may be obtained from an experimental technique, such as X-ray crystallography or NMR. In other cases a theoretical method is employed, such as a conformational search algorithm. A combination of experimenfal and theoretical approaches may also be used. For example, to study the behaviour of a protein in water one may take an X-ray structure of the protein and immerse it in a solvent bath, where the coordinates of the solvent molecules have been obtained from a Monte Carlo or molecular dynamics simulation. 

Tree representation of the conformation search problem for hexane. Unlike the tree in Figure 9.4 the path gth from the root node to any of the terminal nodes is constant. 

Flow chart steps Jbllowed by a random conformational search. 

A comparison of fine different conformational searching algorithms. (Data from [Saunders et at 1990].)... 

Judson R S, W P Jaeger, A M Treasurywala and M L Peterson 1993. Conformational Searching Methods for Small Molecules. 2. Genetic Algorithm Approach. Journal of Computational Chemistry 14 1407-1414. 

Method and a Genetic Algorithm for Conformational Searching. Journal of Computational... 

All of the conformational search methods that were described in Sections 9.2-9.7 have bee used at some stage to explore the conformational space of small pephdes. Here we wi describe some of the methods designed specifically for tackling the problem for peptide and proteins. 

The amount of computation necessary to try many conformers can be greatly reduced if a portion of the structure is known. One way to determine a portion of the structure experimentally is to obtain some of the internuclear distances from two-dimensional NMR experiments, as predicted by the nuclear Over-hauser effect (NOE). Once a set of distances are determined, they can be used as constraints within a conformation search. This has been particularly effective for predicting protein structure since it is very difficult to obtain crystallographic structures of proteins. It is also possible to define distance constraints based on the average bond lengths and angles, if we assume these are fairly rigid while all conformations are accessible. 

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