0.9 Protein-ligand docking, including flexible receptor-flexible  (Page 7/9)

Another use of soft docking models is to improve convergence during energy minimization of the complex by avoiding local minima. In the initial stages of the conformational search the ligand is allowed to overlap with the receptor and nonbonded energy terms are modified to avoid high energy gradients. During the course of the minimization the interactions are then gradually restored to their original values simulating a ligand that is gradually exposed to the field of the receptor. This allows initial ligand/receptor conformations, which due to steric clashes would result in a very high energy penalty, to slowly adapt to each other in a complementary conformation without overlaps. One potential pitfall of this approach is the possibility that the ligand may become interlocked with the protein, leading to failure of the docking procedure. Although the use of soft receptors presents a number of advantages such as ease of implementation and computation speed, it also makes use of conformational and energetic assumptions that are difficult to verify. This can easily result in errors, especially if the soft region is made excessively largeto account for larger conformational changes on the part of the receptor.

Selection of specific degrees of freedom

In order to reduce the complexity of modeling the very large dimensional space representing the full flexibility of the protein, is it possible to obtain an approximate solution by selecting only a few degrees of freedom to model explicitly. The degrees of freedom chosen usually correspond to rotations around single bonds (see Figure 7). The reason for this choice is that these degrees of freedom are usually considered the natural degrees of freedom in molecules. Rotations around bonds lead to deviations from ideal geometry that result in a small energy penalty when compared to deviations from ideality in bond lengths and bond angles. This assumption is in good agreement with current modeling force fields such as CHARMM [12] and AMBER [13] . Selection of which torsional degrees of freedom to model is usually the most difficult part of this method because it requires a considerable amount of a priori knowledge of alternative binding modes for a given receptor. This knowledge usually is a result of the availability of experimental structures obtained under different conditions or using different ligands. If multiple experimental structures are not available some insight can be obtained from simulation methods such as Monte Carlo (MC) or molecular dynamics (MD). The torsions chosen are usually rotations of aminoacid side chains in the binding site of the receptor protein. It is also common to further reduce the search space by using rotamer libraries for the aminoacid side chains