Searching The Conformational Space For Docking - Genetic Algorithms

Genetic Algorithms

Two of the most used docking programs belong to this class: GOLD and AutoDock. Genetic algorithms allow the exploration of a large conformational space – which is basically spanned by the protein and ligand jointly in this case – by representing each spatial arrangement of the pair as a “gene” with a particular energy. The entire genome thus represents the complete energy landscape which is to be explored. The simulation of the evolution of the genome is carried out by cross-over techniques similar to biological evolution, where random pairs of individuals (conformations) are “mated” with the possibility for a random mutation in the offspring. These methods have proven very useful in sampling the vast state-space while maintaining closeness to the actual process involved.

Although genetic algorithms are quite successful in sampling the large conformational space, many docking programs require the protein to remain fixed, while allowing only the ligand to flex and adjust to the active site of the protein. Genetic algorithms also require multiple runs to obtain reliable answers regarding ligands that may bind to the protein. The time it takes to typically run a genetic algorithm in order to allow a proper pose may be longer, hence these methods may not be as efficient as shape complementarity-based approaches in screening large databases of compounds. Recent improvements in using grid-based evaluation of energies, limiting the exploration of the conformational changes at only local areas (active sites) of interest, and improved tabling methods have significantly enhanced the performance of genetic algorithms and made them suitable for virtual screening applications.