RE: AMBER: Average potential energies and conformer ratios

From: Francesco Pietra <>
Date: Mon, 30 Jul 2007 22:09:02 -0700 (PDT)

Hi Ross:

Thanks for all advice, which I'll follow, step by step.

NMR spectra show two conformers in population ratios that depend on the solvent
(without correlation with the dielectric constant value of the solvent), the
best balance (80:20) in CHCl3, H2O and TFE, the worse (96:4) in EtOH and DMSO.

CD spectra are also strongly dependent on the solvent. Unfortunately, neither
1D nor 2D NMR was able to give a measure of the dihedral angles along the
chirality axes, from which CD mainly depends. Therefore, what I am trying to
simulate are the conformers in the given solvent, and I am interested in their
population ratio under the field of the solvent. I started from water not only
because it is the basic solvent in MD, but also because interaction of these
molecules with pharmaceutically-relevant receptors was investigated (not
published) in this medium. Once I understand MD better (which is still the very
problem for me) I plan to examine the system also in explicit DMSO, CHCl3,
EtOH, etc. I'll rely on R.E.DD.B./R.E.D. III for solvent models.

I am also interested in examining the solvation around my conformers,
particularly around an amide side chain. I have no idea how (and if) that could
be done. What I know so far with VMD is limited to "all" and "all not water".


francesco pietra

--- Ross Walker <> wrote:

> Hi Francesco,
> > PM3ESCF= -259.7765
> > PM3ESCF= -257.1894
> > Judging from QM-MM PM3ESCF, a difference of 2.59 kcal/mol
> > between the two
> > conformers is not too far from the experimental value (NMR)
> > of ca 1.9. Though -
> > after what you explained in detail for this type of system -
> > is that average
> > /\PM3ESCF an estimate on which to rely?
> This is a tricky one. The key is whether the contributions to the ESCF
> energy cancel out so that what you recover when you take the difference of
> the averages is the difference between the average conformer one energy and
> the average conformer 2 energy within solvent. I.e. does all the 'noise'
> from the water etc cancel out. I'm really not sure on this as it would take
> working through all the equations to determine this for sure. Maybe others
> on the list can chime in here. One key point if you wanted to use such
> analysis would be to write to the output file more often and calculate a
> cummulative average that you then plot. This would tell you if the average
> was converging or not. At the moment you have no idea if you have done
> enough sampling or not - I.e. take the cumulative average every 100 steps or
> so and see what the fluctuation in this average is with time.
> Do you know what the experimental NMR value was actually measuring?
> Ultimately it might be better to do some form of thermodynamic integration
> where you convert one conformer into the other or make one vanish and the
> same with the other.
> > I am at Amber just to have dynamics. I have already carried
> > out DFT at high
> > functional and basis set level, including vibrational
> > analysis and temperature
> > correction, all in vacuum.
> Okay, so this makes sense then since here you are obtaining solution phase
> data - I would certainly start by running longer simulations - you likely
> want at least 100ps or so I would guess although as above it would be
> important to look at the average energy as a function of time. You might
> want to try reposting this message along more general lines about what you
> can learn by comparing average potential energies since a number of people
> who might be able to offer more insight might be skipping this thread
> thinking it is specific to QM/MM but really the same argument here would
> apply to a classical simulation although the "noise" on EPTOT may be so
> large that you need a significant amount of sampling to obtain an accurate
> difference. This is the "noise" that may be cancelling out when you just
> look at the ESCF value.
> Good luck...
> Ross
> /\
> \/
> |\oss Walker
> | HPC Consultant and Staff Scientist |
> | San Diego Supercomputer Center |
> | Tel: +1 858 822 0854 | EMail:- |
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Received on Wed Aug 01 2007 - 06:07:30 PDT
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