Dear Professor,
Thank you for your clarification. Currently, my calculated DELTA G binding
from MMPBSA is about 1.5 kcal/mol. I plan to conduct multiple short
simulations and later compute the average value
Now I understand that the box size in the simulations does not
significantly affect the results. Therefore, there is no need to precisely
match the number of water molecules. Once the simulation reaches
convergence, the results should be reliable.
Concerning the implicit solvent and vacuum phases, there seems to be some
confusion. When the implicit solvent and vacuum phase (is it the same as
gas phase ?) are used in MMPBSA, does Amber automatically adjust them to
standard conditions? In other words, are they set to 1 M for the implicit
solvent model and 1 bar (or 1 atm) for the gas phase?
I have this concern because the energy correction between the gas phase
standard condition of 1Atm, 298K and the 1M, 298K is about 1.9kcal/mol.
In reaction A+B----> AB this energy difference cannot be cancelled out
because I have two reactants but only one product. Consequently, the DELTA
G gas from MMPBSA should be adjusted by adding 1.9 kcal/mol to align with
the standard conditions. I couldn't find a definitive reference for the
standard conditions of the gas phase and implicit solvent model in Amber.
Thank you once again for your valuable guidance..
Best,
Yang
On Thu, Apr 4, 2024 at 9:53 AM Carlos Simmerling <
carlos.simmerling.gmail.com> wrote:
> yes, you should use the number of atoms without water. keep in mind that
> this is a simple guide, and these calculations will be approximate in the
> best case.
>
> On Wed, Apr 3, 2024 at 9:06 PM Yang Wei via AMBER <amber.ambermd.org>
> wrote:
>
>> Dear Professor,
>>
>> Thank you for your suggestions.
>>
>> I have implemented the autoimage command for the RMSD analysis of the
>> complex, and now the RMSD of each frame is less than 5.
>>
>> Another question is that, when considering the number of frames for the
>> entropy analysis, which should be at least three times the number of atoms
>> in the complex system, should I also include the number of atoms from
>> explicit water? I'm confused because ultimately, in MM-PBSA analysis, all
>> explicit water and contour ions are removed during post-processing.
>>
>> On Mon, Apr 1, 2024 at 12:35 PM Carlos Simmerling <
>> carlos.simmerling.gmail.com> wrote:
>>
>> > in MM-PBSA analysis, you are removing all of the explicit water during
>> the
>> > postprocessing. So as long as the original simulations were reasonable,
>> > there is no need to try to match up the exact # water molecules or even
>> the
>> > solvate command cutoff distance.
>> > if the numerical values that you listed (2 columns) are the rmsd
>> values, I
>> > suspect this is an imaging issue. In your periodic system, molecules get
>> > "wrapped" in the periodic box, but you want to put them back together
>> > before calculating rmsd of a complex. Try using the cpptraj autoimage
>> > command prior to the rms command.
>> >
>> > On Mon, Apr 1, 2024 at 11:36 AM Yang Wei via AMBER <amber.ambermd.org>
>> > wrote:
>> >
>> >> Dear AMBER Community,
>> >>
>> >> I am currently employing MMPBSA with a multiple trajectory approach to
>> >> compute the binding free energy of two systems. The first involves the
>> >> interaction between a protein (123 amino acids/2,047 atoms) and a
>> single
>> >> molecule (132 atoms), while the second entails a protein-protein
>> complex
>> >> (123 amino acids/2,047 atoms and 163 amino acids/2,765 atoms,
>> >> respectively).
>> >>
>> >> 1. For the 1st system, 10 angstrom is used for the solvatebox of the
>> >> complex (protein-molecule), so that 8,938 water (or 26,814 atoms) was
>> >> added. The input for the MD simulation is written as follows:
>> >>
>> >> NVT production 200 ns
>> >> &cntrl
>> >> imin=0, irest=0,
>> >> nstlim=200000000, dt=0.002, ntx=1,
>> >> ntpr=1000, ntwx=1000, ntwr=50000,
>> >> cut=12, ntb=1,
>> >> ntc=2, ntf=2,
>> >> ntt=3, gamma_ln=2.0,
>> >> tempi=300.0, temp0=300.0,
>> >> ioutfm=1, ntwv=-1, ig=-1, iwrap=1
>> >> &end
>> >> &wt
>> >> type='END'
>> >> &end
>> >>
>> >> Currently, I have maintained an equal number of water molecules for the
>> >> complex (protein-molecule), receptor (protein), and ligand (molecule)
>> to
>> >> preserve concentration. However, utilizing 8,938 water molecules for
>> >> ligand
>> >> (a single molecule) appears excessive and computationally wasteful. I
>> did
>> >> a
>> >> test by employing 3000 water molecules for ligands and the resulting
>> >> binding energy difference is only around ~1 kcal/mol. My question is
>> that
>> >> whether it is necessary to employ the same number of water molecules
>> for
>> >> all components, and if the implicit model necessitates an equivalent
>> box
>> >> size as the explicit model.
>> >>
>> >> 2. For the second system, a 10 angstrom solvate box was employed for
>> the
>> >> protein-protein complex, resulting in the addition of 19,629 water
>> >> molecules (or 58,887 atoms). Apart from nstlim=400000000, the input for
>> >> the
>> >> MD simulation remains identical to the first system.
>> >>
>> >> Prior to the MMPBSA analysis, an RMSD analysis was conducted:
>> >>
>> >> parm ../../Ternary_VHL_solv.prmtop
>> >> trajin ../../Ternary_VHL_solv_nvt_prod.netcdf
>> >> reference ../../Ternary_VHL_solv.inpcrd
>> >>
>> >> rms :1-285.N,CA,C reference out rmsd.agr
>> >>
>> >> quit
>> >>
>> >> Upon visualizing the frames (e.g., Frame 92253 and Frame 92254), the
>> >> fluctuations were likely caused by the size of the box.
>> >> .....
>> >> 92251.000 2.9623
>> >> 92252.000 3.0159
>> >> 92253.000 2.9695
>> >> 92254.000 31.2806
>> >> 92255.000 31.2697
>> >> 92256.000 31.3480
>> >> 92257.000 31.2952
>> >> 92258.000 31.3905
>> >> 92259.000 31.4305
>> >> 92260.000 3.0645
>> >> 92261.000 3.0589
>> >> 92262.000 3.0633
>> >> .....
>> >>
>> >> I'm concerned about the potential impact of these fluctuations on the
>> >> MMPBSA analysis and whether enlarging the size of the water box would
>> be
>> >> necessary. This could lead to longer simulation times and require more
>> >> frames for the entropy analysis.
>> >>
>> >> Thank you in advance.
>> >>
>> >> Best,
>> >>
>> >> Yang
>> >> _______________________________________________
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>> >> AMBER.ambermd.org
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>> >>
>> >
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Received on Fri Apr 05 2024 - 07:30:03 PDT
