LigDockCSA: Protein–ligand docking using conformational space annealing

Abstract

Protein-ligand docking techniques are one of the essential tools for structure-based drug design. Two major components of a successful docking program are an efficient search method and an accurate scoring function. In this work, a new docking method called LigDockCSA is developed by using a powerful global optimization technique, conformational space annealing (CSA), and a scoring function that combines the AutoDock energy and the piecewise linear potential (PLP) torsion energy. It is shown that the CSA search method can find lower energy binding poses than the Lamarckian genetic algorithm of AutoDock. However, lower-energy solutions CSA produced with the AutoDock energy were often less native-like. The loophole in the AutoDock energy was fixed by adding a torsional energy term, and the CSA search on the refined energy function is shown to improve the docking performance. The performance of LigDockCSA was tested on the Astex diverse set which consists of 85 protein-ligand complexes. LigDockCSA finds the best scoring poses within 2 Å root-mean-square deviation (RMSD) from the native structures for 84.7% of the test cases, compared to 81.7% for AutoDock and 80.5% for GOLD. The results improve further to 89.4% by incorporating the conformational entropy.

Absolute binding free energy calculations of CBClip host–guest systems in the SAMPL5 blind challenge

“…2. First, we generated the putative binding poses of CBClip and guest molecules in two ways: (1) by slowly creating a guest molecule inside CBClip in the gas phase with a harmonic restraint to keep the guest near the center of mass of CBClip (referred to as “-MD” sets) and (2) by performing docking simulations using the GalaxyDock program (referred to as “-dock” sets), which finds the putative binding poses of protein–ligand, protein–protein and host–guest complexes via highly efficient global optimization [44–47] of the AutoDock4 scoring function [45, 48, 49]. We obtained the initial conformations for the MD simulations from scratch and did not use the conformations provided by the organizers.…”

GalaxySite: ligand-binding-site prediction by using molecular docking

“…Up to three non-metal ligands are extracted from the protein–ligand complex structures of similar proteins detected by HHsearch (16). Ligand-binding poses are then predicted using LigDockCSA (17). …”

“…GalaxySite uses the LigDockCSA (17) protein–ligand docking program that performs global optimization by using the conformational space annealing (CSA) algorithm (17, 20–22). The protein structure is fixed at the initial input or model structure, and the ligand is considered fully flexible.…”

“…The pool is then evolved by generating trial conformations and comparing the trial conformations with the pool conformations, gradually focusing on narrower regions of lower energy in the conformational space. Details on the docking algorithm can be found elsewhere (17). Out of the final pool of 100 structures, the pose with the lowest docking energy in the largest cluster is selected as representative binding pose.…”

“…Open Babel 2.2.3 is used to prepare the ligands for the molecular docking procedure. The molecular docking algorithm for binding-site prediction is implemented in the GALAXY program package (14,15,17,25–28) written in Fortran 90. When a sequence is given as an input, the structure is predicted by GalaxyTBM (14,15) with no additional model refinement.…”