Addressing Protein Flexibility

FLIPDock [121] proposes a novel way of encoding both ligand and protein flexibility in docking. Molecular objects are recursively partitioned into independent nodes from a flexibility tree. Nodes are allowed to move with respect to each other through well-defined motions (shear, twist, screw, etc.), while normal modes are used to treat the node s internal flexibility. Side chain motions are considered classically by 

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Flexibility to address proteins over the wide range of size and pi. 

Virtual screening applications based on superposition or docking usually contain difficult-to-solve optimization problems with a mixed combinatorial and numerical flavor. The combinatorial aspect results from discrete models of conformational flexibility and molecular interactions. The numerical aspect results from describing the relative orientation of two objects, either two superimposed molecules or a ligand with respect to a protein in docking calculations. Problems of this kind are in most cases hard to solve optimally with reasonable compute resources. Sometimes, the combinatorial and the numerical part of such a problem can be separated and independently solved. For example, several virtual screening tools enumerate the conformational space of a molecule in order to address a major combinatorial part of the problem independently (see for example [199]). Alternatively, heuristic search techniques are used to tackle the problem as a whole. Some of them will be covered in this section. 

In an effort to address this issue, the cooperative binding of antifreeze proteins as well as the role of side chain flexibility (14, 15) has been investigated. However, further complications have arisen with the discovery that different antifreeze proteins bind to separate faces or surfaces of an ice crystal (2). It is not surprising then, that a unified hypothesis centered on the molecular mechanism of action has not been proposed. 

It is obvious that a detailed knowledge of the structure of sugar entities, both free and bound to proteins, is indeed relevant from both basic and applied scientific viewpoints. This information may be extracted by different means, including NMR and different reviews have addressed this topic.200 X-ray crystallography has also been widely employed for characterizing free and complexed carbohydrate-binding proteins (for instance, Banerji etal 01). Accordingly, examples of the application of X-ray to the study of these compounds are of prime interest.202,203 However, carbohydrates are often rather difficult to crystallize, probably because of their inherent flexibility. Furthermore, X-ray basically provides only indirect information on the dynamics of the biomolecules and, moreover, for flexible structures, only one conformation may be analyzed. 

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