## Friday, November 21, 2014

### New version of the manuscript

First of all, I want to thank all the contributors and readers for their courage to participate to this project. I am impressed about people's willingness to contribute for such a project. I think that we have proven that this approach can be very effective in our field.

Originally one of the ideas of the project was to improve the manuscript that was published in the arXiv. I have now basically rewritten the original manuscript based on the results published in this blog. You can find the current version of the manuscript here: https://www.dropbox.com/s/kza9ta2kpu54jod/HGmodel_forComments.pdf?dl=0

There is also the version which is constantly updated during the writing process found here:
https://www.dropbox.com/s/0xlxndnh1ezik2g/HGmodel_draft.pdf?dl=0

The current manuscript covers only the results for fully hydrated bilayers, effect of dehydration and effect of cholesterol. The plan is to write a separate manuscript about the ion-lipid interactions.

There are still several open issues and missing details in the manuscript (listed in a todo list in the manuscript). Once these have been sorted out, the manuscript will be published in arXiv and also submission to a Journal will be considered.

All kinds of comments about the manuscript are welcomed from everybody (also from people who are not contributors yet). You can submit your comments by commenting this post. The *tex file of the manuscript is also available in GitHub. If you want, you can directly modify that and make a pull request to include your modifications into the manuscript.

There are some very important practical notes:

Authorship. The authorship of the manuscript will be offered for everyone who has commented the blog, according to the "on the credits post". The final decision on authorship will be made by invited individuals themselves based on their self-assessment of their scientific contribution to the project. I have sent the manuscript to the contributors few days a ago asking if their name should be included in the author list. I have currently included the names of authors who have clearly and directly answered to the question "Will your name be included in the authorlist of the current manuscript?" To become an author you have to straightforwardly answer that question through the email or by commenting this post (i.e. sending simulation details etc. is not interpreted as a yes answer to the question about the authorship).

Comments, questions and contributions. One of the key ideas of this project is that all the discussion about the scientifc content will be done publicly through this blog. This implies also to the comments, questions and contributions regarding the manuscript. Since I was asking contributor's decisions about authorship by email, I got some replies related to the content also by email. Due to the idea of having all the discussion about content publicly available, I will repeat here the comments, questions and contributions I have received by email. Ideally further discussion related to the content of the manuscript will continued by commenting this post.

1) Matti Javanainen commented (translated from Finnish):
Time constants in Gromacs are in ps, not in (ps)^-1.
I would not report real space cut-off's anymore since, at least, in the Gromacs 4.6. and newer they are optimized in the beginning of each simulation, thus the values set in mdp file do not have any practical meaning.

SAMULI: We should check from which version this optimization thing has started.

2) Antti Lamberg asked (translated from Finnish): Why do we have only absolute values in Fig. 2.? In this figure my parameters would be good, however, they have the wrong signs.

SAMULI: The real reason is that the most of the data in Fig. 2 was contributed and the figure was made before we started to look at the signs and stereospecific labeling (largely due to your contributions). We could (and it would be somewhat useful as well) to include also signs and stereospecific labeling into these results. However, it would not change the conclusions made from that figure, i.e. that only CHARMM36, MacRog and GAFFlipid are worth of more detailed studies (now taking into account only published models). For this reason my opinion is that we should not use our time and energy to include all the details into the Fig. 2. My idea is currently that we would leave the attemptions to improve the model for further publications, and I think that in this context we could discuss the issue that there may be a model which has good absolute values, but wrong signs and stereospecific labeling. Since this does not happen in practise with the published models discussed in the current manuscript we can leave this discussion out now.

CONTRIBUTIONS FROM EMAILS:

A lot of information from Matti Javanainen:

Andrea Catte send the simulation details from his simulations (these contained ions, thus they are not used in the current manusript but will be relevant for the manuscript about ion-lipid interactions):

The starting DPPC lipid bilayer, which was built with the online CHARMM-GUI
(http://www.charmm-gui.org/), contained 600 lipids, 30 water molecules/lipid, Na+ and Cl- ions (150 mM NaCl). The TIP3p water model was used to solvate the system. AA MD simulations of DPPC lipid bilayers were performed at ten different  temperatures (283, 298, 303, 308, 312, 313, 314, 318, 323, and 333 K) using the GROMACS  software package version 4.5.5 and the S tockholm lipids (S lipids) force field parameters for phospholipids. After energy minimization and a short equilibration run of 50 ps (time step 1fs), 100 ns production runs were performed using a time step of 2 fs with leap-frog integrator. All covalent bonds were  constrained with the LINCS  algorithm. Coordinates were written every 100 ps. PME with real space cut-off at 1.0 nm was used for Coulomb interactions. Lennard-Jones (LJ) interactions were switched to zero between 1.0 nm and 1.4 nm. The neighbour lists were updated every 10th step with a cut-off of 1.6 nm. Temperature was coupled separately for upper and bottom leaflets of the lipid bilayer, and for water to one of the temperatures reported above with the Nosè-Hoover thermostat using a time constant of 0.5 ps. Pressure was semi-isotropically coupled to the atmospheric pressure with the Parrinello-Rahman barostat using a time constant of 10 ps. The last 40 ns of each simulation was employed for the analysis of DPPC choline and glycerol backbone order parameters.

Alexander Lyubartsev sent some simulation details:

Here are details of simulations with Hörberg et al force field:

lipid       Nl    Nw    T(K)      t-sim      t-an

DMPC        98   2700   303         75       50
POPC       128   3840   303        100       80

DMPC simulations are from ref 19 (Högberg et al)
POPC simulations are from A.L.Rabinovich, A.P.Lyubartsev J.Phys.
Conference series
510 , 012022 (2014)

Simulation details:

Time step 2fs, Ewald summation,
cut-off 14 Å, update of neighbour list each 10 steps,
Nose-Hoover thermostat,  Parrinello-Rahman barostat,
semi-anizotropic pressure coupling,
long-range isotropic pressure correction

Final note by Samuli: This suggestion in Page 7 in the manuscript:
"Interestingly, the probability of the gaughe
conformations correlates with the order parameter difference
between the
$$\beta$$ and $$\alpha$$ segments: the larger the gaughe fraction
the larger the order parameter difference. This suggestion together
with the results in Fig. 3 would indicate that the correct
gaughe-trans fraction for N- - -O dihedral is larger than in
GAFFlipid but smaller than in CHARMM36."

is not supported by the recent results in the blog from the new model by
Tjörnhammar and Edholm. I will rewrite this discussion.