I have a protein ligand complex. How can I calculate the contribution of the individual residues to the overall binding of the inhibitor in the protein's binding pocket? I need it in two cases: (1) the complex is from a crystal structure, (2) the complex is from docking.
Thanks.
Hi Rajiv,
The MMGBSA module implemented in AMBER can do that. See the following tutorial:
http://ambermd.org/tutorials/advanced/tutorial3/py_script/section6.htm
Hi Rajiv,
First you need to do molecular dynamics simulations to validate the stability of the complex. You can use Gromacs software which is freely available. Once you finished MD simulation, perform MM-PBSA analysis to find out which residues are playing an important role in stabilization of substrate in the binding pocket.
https://rashmikumari.github.io/g_mmpbsa/
Good luck
Gaurao
Dear Rajiv,
The model can be further refined using the Desmond molecular dynamic simulations (MDS) of Schrödinger suit ..With system builder of the Desmond module, the model can be incorporated in an orthorhombic periodic boundary box and then you can solvate that by using the SPC water model... This can be neutralized with some number of Na+ ions based on the total charge of the model and to that system some amount of salt can be added. This can be simulated using the dynamic simulation step of the Desmond module.
The simulations should carried out using NPT ensemble, at 300 K temperature, one atmospheric pressure and then the entire system should relax by using the default protocol.
The system should carried for 100 ns simulation time period and the trajectory should obtaine from that simulation run could be analysed.
For Ligand preparation in Schrodinger
The structures for the molecules should retrieve from Pubchem database and LigPrep tool of Schrödinger suite with OPLS_2005 as a force field should use for preparation.
The ionization states of these molecules can be generated at pH 7.0±2.0 using Epik module and some number of possible stereoisomers generation per ligand can select.
For Docking studies
The refined model obtained from the simulation studies can further prepared using the protein preparation wizard by addition of hydrogens and bond orders assignment. The model may optimize and minimize by using force fied OPLS_2005 with RMSD of some Å (1 Å=0.1 nm). A grid box will generate around the important amino acids reported previously using the receptor grid generation protocol of the Glide module. The prepared protein and molecules can dock covalently using the covalent docking protocol of the glide module.
After finding out which amino acid is playing crucial role in the stabilization of substrates bin the binding pocket you can do Inilico mutational analysis for the cross evaluation of the model built for that,
The model can point mutate with respective amino acid replacing the key amino acid of the catalytic traid and then mutated model may dock with selected substrates under the similar experimental conditions opted above then you will found no covalent bond formation...
https://m.facebook.com/photo.php?fbid=331788824220439&id=100021679728035&set=gm.2186793694665568&source=48
Register there.. it may be useful for you..
You can also use Grinn that can compile residue interaction-energies.
https://grinn.readthedocs.io/en/latest/introduction.html
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