Thursday, July 27, 2017

Quantifying the effect of bound charge on headgroup order parameters

[UPDATED 8.12.2017]

Electrometer concept is used in NMRlipids II and IV to measure the amount of bound ions in lipid bilayers. It is based on empirical observations by Seelig et al. that the PC lipid headgroup order parameters for alpha and beta carbons depend linearly in bound charge. In NMRlipids II project the concept was observed to be qualitatively valid also in simulations, as seen in Fig. 1.

Fig 1: Change of order parameters as a function of bound charge analyzed from simulations with various ions in NMRlipids II publication (Fig. 3.)

However, the comparison of this data with experiments was not straightforward, because it simultaneously depends on the amount of bound ions, definition of bound ion and sensitivity of the headgroup order parameters to bound ions. The issue was discussed during NMRlipids II project and also in the supplementary information of the publication (section 3), but simulations with cationic surfactants were not performed to quantify the sensitivity of the headgroup response to bound charge. 

Because the issue significantly complicates the usage of electrometer concept in simulations, as also seen now in NMRlipids IV project, I performed a simulation of PC lipid bilayer mixed with different mole fractions of cationic surfactants (more specifically dihexadecyldimethylammonium bromide, C12C16+N2CBr-). The advantage of such system is that essentially all the ions (i.e. charged surfactants) can be assumed to be bound in bilayer, thus the amount of bound charge is known exactly. Thus, the system can be used to quantify the lipid headgroup sensitivity to bound charge.

The headgroup order parameters from Lipid14 simulations and experiments as a function of cationic surfactant are shown in Fig. 2.

Fig 2: Headgroup order parameter changes as function of cationic surfactant from simulations with Lipid14 (files available at 0.10.2,0.3,0.42 and 0.5), CHARMM36 and experiments.
The results show that the headgroup order parameter response to bound charge is approximately linear also in simulations. However, headgroup is slightly too sensitive to the bound charge in Lipid14 model. This indicates that some of the overestimated order parameter decrease for Lipid14 with CaCl2 concentration in NMRlipids II publication may be due to the headgroup response on bound ions instead of overestimated binding affinity.

My feeling is that we need to do such test, at least, also for CHARMM36 model, for which data about Ca2+ binding in negatively charged lipid bilayer was recently reported.

[UPDATE 8.12.2017] CHARMM36 results added in Fig. 2 show better agreement with experiments. This has to taken into account when using headgroup order parameters to compare binding affinity between simulations and experiments. 


  1. How/where did you obtain the force field for dihexadecyldimethylammonium?

    Small note: From the GitHub files it seems this was not run with Br-, but with Cl-. Thus should probably not refer to it as bromide?

    1. Automated topology builder [1] was first used to create
      the structure of dihexadecyldimethylammonium bromide molecule. AmberTools program [2] was then used to generate the Amber-type force fieLd parameters. The parameters were converted to the Gromacs format by using acpype tool [3]. The partial charges were then manually modified to approximately correspond to their equivalent
      segments in Lipid14.

      [1] A. K. Malde, L. Zuo, M. Breeze, M. Stroet, D. Poger, P. C. Nair, C. Oostenbrink, and A. E. Mark, Journal of Chemical Theory and Computation 7, 4026 (2011).
      [2] D. Case, D. Cerutti, T. Cheatham, III, T. Darden, R. Duke, T. Giese, H. Gohlke, A. Goetz, D. Greene, et al., AMBER 2017 (2017), university of California, San Francisco.
      - AnteChamber PYthon Parser interfacE. (2017), manuscript submitted.

      Yes, I think that there was no Br- parameters available so I used Cl- as counterion. This must be somehow mentioned, indeed.


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