Hi MS Community,
This is regarding calculating Solvation Free Energy (SFE) using Forcite module.
So, basically I wanted to calculate SFE of Paracetamol (PCM) in Acetone (and in various other solvents and wanted to corelate it with the experimental values at 303.15K).
I made two attempts with Acetone as solvent.
Attempt-1:
PCM molecules- 1
Acetone- 100
SFE turned out to be -94.295 kcal/mol which is highly unlikely.
Now if you apply the formula, Solubility= exp( -SFE / RT) (provided by @TM in one of the older threads) , you get solubility as 1.44*10^67 mg/mL which is impossible for any API.
FYI, solubility of PCM in acetone at 303.15K is 88.3mg/mL.
So, I improved my simulation and made attempt-2.
Attempt-2:
- AC Construction: PCM- 10 molecules, Acetone- 1000 molecules
Force Field- COMPASSIII, Electrostatic- Group based, van der waal- Atom based.
2. Forcite GeomOpt: Algorithm- Smart, Iterations- 5000, Electrostatic and van der waal- Atom based, Quality- Fine
3. Dynamics: a) first NPT for 100ps at 303.15K, Initial Velocities- Random, Electrostatic and van der waal- Atom based, Quality- Fine
b) second NVT for 100ps at 303.15K, Initial Velocities- Random, Electrostatic and van der waal- Atom based, Quality- Fine
4. Solvation Free Energy: Contribution- All, Algorithm- Thermodynamic Integration, Eq Steps- 50000(increased 10 times from default value), Production steps- 100000 (increased 10 times from default value),
Coupling parameter: Start- 0, End- 1, Steps- 20.
The results I am getting from attempt-2 are given below:
Ideal free energy : 815.936 kcal/mol
Van der Waals free energy : -1.679 kcal/mol
Electrostatic free energy : -1594.833 kcal/mol
Solvation free energy : -780.576 kcal/mol.
As one can see that the new SFE is even more unlikely than the previous one, even though I corrected many things, ran longer simulations, increased eq and production steps, and also created a system with increased number of molecules.
Kindly suggest me how can I approach this challenge and get values which are closer to experimental values.
