Tuesday, April 7, 2020

NMRlipids VI: Polarizable force fields

The primary goal of the NMRlipids Project is to find atomic resolution MD simulation force fields that correctly capture the lipid headgroup structures of biologically relevant lipids, and their interactions with ions and other biomolecules.

Current results from the NMRlipids Project indicate that none of the existing force fields correctly captures the lipid headgroup structures (NMRlipids I and IVa). However, the differences between PC, PE, PG and PS headgroup structures are roughly reproduced in CHARMM36, and the description of ion binding to PC and PS headgroups is substantially improved when electronic polarizability is implicitly included using the electronic continuum correction (ECC).

So far, the NMRlipids Project has focused on force fields that lack electronic polarizability. However, the number of available polarizable lipid force fields is increasing, and our PC and PS simulations with ECC suggest that the electronic polarizability may be an essential player in lipid–ion interactions. For these reasons, Batuhan Kav, an active NMRlipids contributor, has suggested the NMRlipids community to make a systematic review and benchmark study of the available polarizable lipid force fields. To this end, we hereby launch the NMRlipids VI project. It will follow the normal NMRlipids rules, with the exception that Batuhan Kav will mainly push the project and thus be the corresponding author.

Note that besides its primary goal, the NMRlipids Project has produced the largest publicly available collection of lipid bilayer MD simulations (indexed also at www.nmrlipids.fi) and evaluations of lipid headgroup force field quality against NMR experiments. To strengthen this side of NMRlipids, we will in NMRlipids VI test a new data contribution, indexing and analysis protocol that paves the way toward the planned leap to the NMRlipids Databank.

As in all NMRlipids projects, the contributions to NMRlipids VI can be made by commenting blog posts related to this topic or by contributing to the related GitHub repository. The GitHub repository already contains a draft review by Batuhan Kav on the published simulations on polarizable lipid force fields. In addition, a python script and stepwise instructions on how to contribute data are available.

In the published literature on polarizable force fields (see Batuhan's draft review), the acyl chains have already been evaluated against NMR order parameter data, but the quality of headgroup structures and ion binding remains largely untested. As a first step to do this test, we need trajectories from polarizable lipid bilayer simulations. During initial attempts to run lipid bilayer simulations with polarizable force fields, it turned out to be significantly more complicated than for non-polarizable force fields. Therefore, we specifically ask contributions from people, who already have data from lipid bilayer simulations with polarizable force fields, or know how to run these in practise. The polarizable lipid force fields that we are aware of are:
If you have access to lipid bilayer simulations using these or other polarizable lipid force fields, and are willing to contribute to the project, please contact us and/or contribute the data according to the instructions. Currently our analysis script works for data from Gromacs and NAMD, but our goal is to accept data from any MD engine. Do not hesitate to give us feedback on the data contribution and analysis, or to develop it further by yourself on GitHub.

Batuhan Kav
Markus Miettinen
Samuli Ollila

6 comments:

  1. Hello,

    I have generated a trajectory of pure POPC using the Drude polarizable model with OpenMM simulation package. The trajectory files are at

    https://doi.org/10.5281/zenodo.3865283

    and the analysis results are at

    https://github.com/NMRLipids/NMRlipidsVIpolarizableFFs/tree/master/Data/tmp_initial_drude_popc

    The initial data shows that the Drude and Charmm36 force fields behave very similarly when it comes to the order parameters without any ions.

    One thing we can try to check is how these force fields differ with respect to the ion binding. From NMRLipids Lipid-Ion interactions project, we already know how Charmm36 behaves. My suggestion would be to run POPC simulations with the Drude model at 0, 350, 450, 650, and 1000 mM NaCl or CaCl2 concentrations. If no one is interested in running these simulations, I will run them.

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    Replies
    1. Where is the data for CHARMM36 POPC taken from? It does not look like a typical results we have got from this force field. Alpha and beta carbon in CHARMM36 are typically quite close to experiments and do not exhibit any forking.

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    2. Hi Samuli,

      There was a mistake in the plot for the Charmm36 results. I have updated the plots on GitHub.

      Prior to a simulation with Drude force field, I need to run 100-200 ns of equilibration with Charmm36. I calculated the order parameters from this simulation, using the last 100 ns of a total 200 ns trajectory.

      The order parameters for the Charmm36 now seem close to what we expect.

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    3. Thanks. It is interesting that the CHARMM Drude model has this large forking in the order parameters. In the parametrization publication they have tuned the headgroup dihedrals to capture these order parameters correctly. However, they report only absolute values and I cannot see any forking in their results.

      Anyway, I agree that these simulations with ions would be highly interesting. Are there any publications where simulations are ran with ions using this model?

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    4. I'm not sure how they calculate the order parameters for alpha and beta hydrogens. I am also not aware of any publication for Drude lipids + ions.

      Initially I will look at the NaCl binding behavior of the Drude POPC model.

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  2. Hello,

    I finished running the simulations of pure POPC (72 x 72) membrane at 350mM, 450mM, 650mM, and 1000mM NaCl (or CaCl2 -- 1000mM simulations for CaCl2 not available yet) concentrations using the Drude polarizable force field. The trajectories are available under Zenodo (links follow below). My plan is to finish analyzing them by early October.

    https://zenodo.org/record/3997054
    https://zenodo.org/record/3994327
    https://zenodo.org/record/3991895
    https://zenodo.org/record/3991507
    https://zenodo.org/record/3994138
    https://zenodo.org/record/3994321
    https://zenodo.org/record/3994331

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