Parameterization of the CHARMM All-Atom Force Field for Ether Lipids and Model Linear Ethers

Area of Science:

• Biomolecular simulations
• Computational chemistry
• Lipid biophysics

Background:

• Linear ethers and ether-linked phospholipids are vital in industrial, medical, and biological contexts, particularly in cell membranes.
• Accurate molecular modeling requires precise force field parameters for these structures.
• Existing CHARMM (C36) parameters may not fully capture the behavior of ether linkages.

Purpose of the Study:

• To refine CHARMM (C36) force field parameters for linear ethers.
• To develop new parameters for ether-linked phospholipids, specifically 1,2-di-O-hexadecyl-sn-glycero-3-phosphocholine (DHPC).
• To improve the accuracy of molecular dynamics simulations involving ether-linked lipids.

Main Methods:

• Utilized ab initio calculations to derive new partial-charge and dihedral parameters.
• Developed and validated a new CHARMM force field, termed C36e.
• Performed molecular dynamics simulations of DHPC and 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayers.
• Compared simulation results with experimental data from X-ray and neutron scattering.

Main Results:

• The C36e force field accurately represents the dihedral potential energy landscape of linear ethers.
• C36e improves the accuracy of simulated densities and free energies of hydration for linear ethers.
• Simulations with C36e show increased water penetration and larger surface area per lipid in DHPC bilayers.
• Ether linkages enhance water organization in the headgroup region compared to ester linkages.

Conclusions:

• The C36e force field provides a more accurate representation of ether-linked lipids.
• Improved simulations reveal structural differences between ether- and ester-linked lipid bilayers.
• The findings offer insights into the lower water permeability of ether-linked lipid bilayers, relevant for biological membranes.