Friday, July 1, 2016

NMRlipids III: Preliminary observations

[updated 19.10.2016]

I have started to assemble the NMRlipids III manuscript. The project is initiated from the discussion started by Peter Heftberger (see Data Contributions page, discussion from December 1, 2014). Heftberger et al. compared x-ray scattering form factors with results from CHARMM36 simulations and concluded that the results did not quite agree (see the report). This was slightly surprising since simulation literature typically reports good agreement with experiments for form factor data, also for CHARMM36 with cholesterol. In the subsequent discussion we decided to take a simple two component lipid bilayer to check how accurately lipid mixtures can be described by atomistic resolution molecular dynamics simulations. For such system we chose the POPC/cholesterol mixtures up to 60 mol% of cholesterol. Extensive NMR data for this systems is already published, extensive simulation data sets are already collected in NMRlipids I and extensive scattering form factor data was reported in this blog by Georg Pabst et al. (July 3, 2015, comment in About page).

I have now started to collect this data in the manuscript (available from GitHub according to the current workflow of the project). All the data is not there yet, but some preliminary results can be already discussed. Some results for order parameters and form factors, and preliminary observations are shown here:

Figure 1: Acyl chain order parameters from experiments and  different simulations for pure POPC and POPC with 50mol% of cholesterol.
Figure 2: Form factors from experiments and simulations with different cholesterol concentrations in POPC bilayer. The Experimental form factor amplitudes are not scaled to match with simulations, thus mainly the locations of minima should be compared.

Preliminary observations:

CHARMM36: The order parameters are too large in both simulations, with and without cholesterol. The form factor gives minima at too small q values. This is not expected from the parametrization publications. However, the form factor result is pretty similar to the one report reported by Heftberger et al. (simulations ran with NAMD). More detailed discussion about reproducing some CHARMM36 results is in GitHub issue. [Update 19.10.2016] as shown in the GitHub issue, the overestimation is largely (but not completely) due to the usage of older version of Gromacs in the original results. The results from Gromacs 5 are now used in the manuscript.

Berger/Höltje: The order parameters in pure POPC are in very good agreement with experiments, as often reported in the literature. However, form factor has minima at too high q-values. With 50mol% of cholesterol the order parameters are too high, as reported before. However, the form factor minima are surprisingly good with 50mol% of cholesterol. My preliminary interpretation is that the model has too large area per molecule in pure POPC and too strong condensing effect of cholesterol. This leads to good agreement in form factor with large cholesterol concentration but order parameters are then too large. This would also indicate that the relation between order parameters and packing density would not be right in this model. However, more careful analysis is needed.

MacRog: Order parameters are not in good agreement in neither of the systems, with or without cholesterol. Form factors still to be calculated.

Things to be done:
  1. I would like to plot the electron densities from simulations together with the results from the SDP model used for the scattering data. The SDP profiles are available in the delivered data set, but only in *eps format. Would it be possible to deliver these also in ASCII format?
  2. In addition to the simulation data we already have, at least Slipid and Lipid14 models have compatible cholesterol models. At least some data from these models is almost necessary for this project. The corresponding simulations are already ran for Lipid14 and we could take the order parameters from the publication. However, for form factors we would need the simulation trajectories (or someone delivering the results). [Update 19.10.2016] Slipids data are already delivered. Lipid14 data is in progress.
  3. There is also experimental form factor data available for other binary mixtures than POPC/chol. The data for DOPC/CHOL and DPPC/CHOL mixtures was delivered by Heftberger et al. (see also report) and there seems to be more in the literature. If someone delivers corresponding simulation data, the comparison would be a good complement for the extensive POPC/chol set.
  4. The order parameters for POPC (preferably in 303K or close) from CHARMM36 simulation ran with NAMD or CHARMM would be useful to check if they are the same as from Gromacs. More discussion in GitHub issue. [Update 19.10.2016] NAMD data and much more is delivered throught the discussion in GitHub. The conclusion seems to be that Gromacs 5 gives more or less consistent results with other codes.
I will go now for summer vacation and continue working on this in the beginning of August.