Molecular Dynamics Simulation of the Interaction Between Polyfluoroalkyls and Dipalmitoylphosphatidylcholine bilayer

Jeffrey Ge(jeff.90g@gmail.com)1, Zhiqiang Shen2, and Ying Li21. Science, Discovery, and the Universe Scholars Program, University of Maryland

2. Department of mechanical Engineering, University of Connecticut

Introduction and Context

Methods

I Thank the National Science Foundation (NSF) Research Experiences for Undergraduates (REU) Program for making this research possible. I would also like to thank Zhiqiang Shen and Ying Li for providing advice in the running of simulations.

Conclusion and Future Work As expected, in all free penetration tests the polymers managed to penetrate into the lipid bilayer. The free energy analysis can be used to explain many experimental findings. • The free energy analysis demonstrate a small

(<3 kcal/mol) energy barrier to polymer penetration

• A significantly larger (~7 kcal/mol) barrier to exiting explains how such molecules may linger in wildlife for long periods of time

• Experiment has shown that longer chain PFAs tend to have higher toxicity. Free energy analysis shows this is due to a lower energy barrier to entry.

Since data for all simulated cases confirmed prior experiment is demonstrate that molecular dynamics can be an accurate tool for characterizing these interaction. In addition, since these findings were shown for all simulated cases it is likely that they generalize to PFAs in general. Moving forward different types of solvents and/or lipids could be tested to confirm these findings.

1. Free penetration Trials

• Free penetration tested by placing polymers away from surface

• All polymers eventually penetrated DPPC bilayer

• Shorter length polymers exhibited lower rates of penetration

2. Embedded Polymer Effects

• All atom simulation

• Uses “force field” to model dynamics of interaction

• Parameters based on experiment and calculations

• The CHARMM36 force field used for focus on lipid modelling

• VMD was used to create and ensure correct initial configurations.

• TCL scripts were used to assist with configuration generation.

Running SimulationsInitial configurations from VMD were run on LAMMPS software with the following settings.

Parameter ValueTimestep 1 fsPressure 1 atmTemperature 310 KSHAKE Tolerance (H2O only) 1e-6 nm

Simulations were run at the High Performance Computing facilities at the University of Connecticut until at least 10 ns had elapsed

• Perfluoroalkyls are a class of organic molecules containing carbon-fluorine bonds.

• Fluorine bonds lead to very high chemical stability.

• Recent studies have shown accumulation in the environment, and mild toxicity.

• Molecules known to stay in organisms for years

• Reactions to small and to quick to determine experimentally due to speed and scale

• Molecular dynamics provides a method of accurately modelling the molecular interactions and observing them in detail

Molecular Simulation of molecules

Free Energy Analysis

Conclusion and Future Work

Simulation Results and Limitations

Acknowledgements

• Slight polymer aggregation observable• No polymers escaped bilayer • Heads still affixed to lipid surface

PFHS PFOA

PFNA PFOS

4 ns

PFHS PFOA

PFNA PFOS3. Quantitative Data

Radi

al D

ensi

ty F

unct

ion

Distance (nm)

g(Di

stan

ce)

0 20 40 600

0.51

1.52

2.53

3.54

4.55

PFOS PFHSPFOA PFNA

• Shorter polymer lengths exhibited less aggregation• Matches prediction based on ionic interaction

• High polymer concentration at membrane barrier• Concentration drops to 0 at center

Dens

ity D

istr

ibut

ion

Free energy analysis was done using umbrella sampling. The free energy diagram explains many other observations.• Small energy barrier to penetration• Lowest energy is when polymer is inside

membrane • A second energy barrier exists near the center

plane of the membrane

Free energy of PFOA

Perfluorononanoic acid (PFNA)

perfluorooctanoic acid (PFOS)

perfluorooctane sulfonic acid (PFOS)

perfluorohexane sulfonic acid (PFHS)

4 ns

Initial Configurations