I would appreciate people's thoughts on a methodology consideration.
We're docking several thousand small molecules at a specific location on the receptor. We're using Autodoc Vina to reduce the library to e.g., 20 compounds. Then, further reduction follows using generalised Born and surface area solvation (MM/GBSA), etc.
This is my concern. The crystal structure is a substrate-bound enzyme. Those that prepared the structure mutated Glu to Gln to prevent activation. This single-point mutation is far from where we are docking the compounds e.g., > 4 nanometres. We are considering what our risks and limitation in our study are before running anything. Will an in silico modification (reverting from Gln to Glu) in the crystal structure affect calculation performed by Autodock (vina of AD4) if those changes are outside the grid box in which docking calculations are performed?
I understand the calculations performed by Adutodock/Vina are stochastic to a degree, so a direct comparison of how that mutation affects the results would be tough to produce. However, is there any merit in performing a before and after screening on the receptor, even if that change is far from the docking site?
This is an intriguing question. First, defining the protein's binding pocket by setting the grid box does not necessarily stop the ligand from interacting with other residues outside the grid box. Hence, mutating the residue in silico could have a potential impact on the docking scores which would be a major criterion in screening out the small molecules.
Also, taking into consideration the charge of the wildtype and mutant proteins, the modification of the protein would perturb the charge of the protein and could potentially have an impact on the interaction profiles of the protein with the compounds.
It will be good to perform both pre- and post-modification docking on the protein to take into account the potential impact of the residue change. Furthermore, I would advise you to get the sequence of the protein and conduct homology modelling using the crystal structure you currently have as the template as opposed to conducting modification using software like Chimera and PyMol.
- Badges
- Science topic
- Similar topics
- Phytochemistry
- Extracts