![]() In the alchemical pathway as seen above, there are four stages along our thermodynamic cycle. Since we are exploring two possible pathways for this problem, both pathways will be explored for their end states. If you turn on the restraints too quickly, you will have poor sampling of the torsion angles and thus the results will not converge to the correct results. It is not clear which choice is the best in general. This will require more intermediate states but may be more efficient in the long run since you will have shorter correlation times after the restraints are added. You could alternately apply the restraints before doing any kind of decoupling actions. In the methods discussed above, the restraints were applied as the decoupling process occurred. Harmonic orientational restraints are placed on six degrees of freedom: one distance, two angles, and three torsions these are determined by the location of three ligand and three protein atoms. ![]() This can be done in either implicit or explicit solvent but is shown implicitly to avoid clutter. This cycle is shown below where the light blue background represents the solvent environment. ![]() Remember, we do not want to remove the ligand from the universe, just its interactions with the protein. We then recouple the ligand with its new solvent box and complete the cycle. ABDULKASEM ALCHEMISTRY FREEThis transfer has a zero free energy cost since the ligand is not interacting at all. We can then transfer this "ghost" molecule from the solvent box with protein to a solvent box with no protein. Note that we do not annihilate the ligand by turning off intramolecular interactions, just intermolecular ones. We first start by decoupling the ligand from the surrounding environment, both protein and solvent. ![]() The alchemical cycle starts with the ligand bound to the protein to make up the complex fully interacting with the environment. For our simulation, we can use either the pulling method or the alchemical path. ![]()
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