I performed a 100ns run for several drug candidates, and i wanted to check their average binding energy using g_mmpbsa. the thing is that g_mmpbsa gave me a very high positive energy for a my reference compound which is a known inhibitor as follows:
#Complex Number: 1
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SUMMARY
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van der Waal energy = -225.720 +/- 13.278 kJ/mol
Electrostattic energy = 3866.697 +/- 82.399 kJ/mol
Polar solvation energy = -637.863 +/- 87.628 kJ/mol
SASA energy = -18.475 +/- 0.895 kJ/mol
SAV energy = 0.000 +/- 0.000 kJ/mol
WCA energy = 0.000 +/- 0.000 kJ/mol
Binding energy = 2984.639 +/- 65.708 kJ/mol
I noticed the problem to be in the electrostatic energy term. after some research I came to know that to overcome such overestimation for highly charged systems. I should use a higher dielectric constant. so these results was at dielectric constant of 2. So, I went for 4,8, and 16 on a shorter range of the trajectory. the electrostatic term kept decreasing and the binding energy as well but stayed positive for constant at 4, and 8. for constant at 16, it gave me binding energy with a negative value ~ - 250. but when using constant 16 with another less stable candidate it gave me ~ - 350. So, I concluded that the electrostatic term is still overestimated so that it affects the relative values between the candidates. here, I went for a very high dielectric constant of 50 to drastically decrease the effect of the electrostatic term. So, at constant 50, the reference compound gave a binding energy of ~ -710, while the less stable molecule gave ~ - 650.
this is the output for the reference compound at constant 50 :
#Complex Number: 1
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SUMMARY
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van der Waal energy = -226.401 +/- 9.161 kJ/mol
Electrostattic energy = 154.710 +/- 2.537 kJ/mol
Polar solvation energy = -620.464 +/- 21.843 kJ/mol
SASA energy = -18.605 +/- 0.766 kJ/mol
SAV energy = 0.000 +/- 0.000 kJ/mol
WCA energy = 0.000 +/- 0.000 kJ/mol
Binding energy = -710.760 +/- 23.953 kJ/mol
so now it gave a right relationship between the two molecules. the question is there something wrong with what I did? is it reliable to go for such high dielectric constant =50? is there a better way to fix this ?
thanks in advance
"Analysis on a large set of proteins shows that (a) the average dielectric constant inside the protein is relatively low, about 6-7, and reaches a value of about 20-30 at the protein's surface, and (b) high average local dielectric constant values are associated with charged residues while low dielectric constant values [with] the regions occupied by hydrophobic residues."
Article On the 'Dielectric "Constant" of Proteins: Smooth Dielectric...
Thanks for your answer, but actually, my system is an RNA riboswitch not protein. in addition, it is highly charged i needed to add ~ 117 Na atoms to neutralize the system. So, what do you think? Is what i did is reliable?
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