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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Received on Mon Apr 01 2024 - 09:00:02 PDT
