Docking Studies
Docking and protein structure preparation was performed on Molecular Operating Environment (MOE 2015.10 and 2016.08) from Chemical Computing Group, Canada. Protein-Ligand docking was designed such that the ligands are placed in the site using the Triangle Matcher method, and ranked with the London ΔG (Wright, Anderson, Shadnia, Durst, & Katzenellenbogen, 2013) scoring function. The initial poses and score were then refined for energy minimization in the binding pocket and rescored using GBVI/WSA ΔG (Corbeil, Williams, & Labute, 2012) scoring function under the Amber12:EHT forcefield set. The target protein and ligands were allowed to sample alternative conformations to allow for induced-fit binding of protein-ligand complex. The highest docking score conformation was used in molecular dynamics (MD) simulation and a final binding affinity reported from the ensemble average using GBVI/WSA ΔG calculation. Accessible solvent area (ASA) was calculated from a single molecular structure using a lattice and a 0-potential contour of the van der Waals potential. Using the median of each potential value as the iso-contour cutoff, the surface was then extended to adjacent grid triangles to smoothen the patch transition (Jorgensen, Maxwell, & TiradoRives, 1996; Wildman & Crippen, 1999). Docking scores were determined for antibody molecules 1, 2, and 3 all IgG1 (mAb1 (pI = 7.59), mAb2 (pI = 7.96), and mAb3 (pI = 8.38)) and protonated at pH 5.5.