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More information about some of these proteins and other proteins motions can be found at the following links:
Although it has been clearly established that a protein is able to undergo conformational changes during the binding process, most docking studies consider the protein as a rigid structure. The reason for this crude approximation is the extraordinary increase in computational complexity that is required to include the degrees of freedom of a protein in a modeling study. There is currently no computationally efficient docking method that is able to screen a large database of potential ligands against a target receptor while considering the full flexibility of both ligand and receptor. In order for this process to become efficient, it is necessary to find a representation for protein flexibility that avoids the direct search of a solution space comprised of thousands of degrees of freedom. What follows is a brief review of the different representations that have been used to incorporate protein flexibility in the modeling of protein/ligand interactions. A common theme behind all these approaches is that the accuracy of the results is usually directly proportional to the computational complexity of the representation. The different types of flexibility representations models are grouped into categories that illustrate some of the key ideas that have been presented in the literature in recent years. However it is important to note that the boundaries between these categories are not rigid and in fact several of the publications referenced below could easily fall in more than one category.Perhaps the simplest solution to represent some degree of receptor flexibility in docking applications is the use of soft receptors. Soft receptors can be easily generated by relaxing the high energy penalty that the system incurs when an atom in the ligand overlaps an atom in the receptor structure. By reducing the van der Waals contributions to the total energy score the receptor is in practice made softer, thus allowing, for example, a larger ligand to fit in a binding site determined experimentally for a smaller molecule (see Figure 6). The rationale behind this approach is that the receptor structure has some inherent flexibility which allows it to adapt to slightly differently shaped ligands by resorting to small variations in the orientation of binding site chains and backbone positions. If the change in the receptor conformation is small enough, it is assumed that the receptor is capable of such a conformational change, given its large number of degrees of freedom, even though the conformational change itself is not modeled explicitly. It is also assumed that the change in protein conformation does not incur a sufficiently high energetic penalty to offset the improved interaction energy between the ligand and the receptor. The main advantage of using soft receptors is ease of implementation (docking algorithms stay unchanged) and speed (the cost of evaluating the scoring function is the same as for the rigid case).
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