A Parameterization of Cholesterol for Mixed Lipid Bilayer Simulation within the Amber Lipid14 Force Field

Abstract

The Amber Lipid14 force field is expanded to include cholesterol parameters for all-atom cholesterol and lipid bilayer molecular dynamics simulations. The General Amber and Lipid14 force fields are used as a basis for assigning atom types and basic parameters. A new RESP charge derivation for cholesterol is presented, and tail parameters are adapted from Lipid14 alkane tails. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers are simulated at a range of cholesterol contents. Experimental bilayer structural properties are compared with bilayer simulations and are found to be in good agreement. With this parameterization, another component of complex membranes is available for molecular dynamics with the Amber Lipid14 force field.

Predicted Decrease in Membrane Oxygen Permeability with Addition of Cholesterol

“…This similarity was initially puzzling because prior EPR experiments had estimated POPC/cholesterol to be about three times less permeable to oxygen than pure POPC [9]. Our simulation systems show strong agreement with other experimental measurements, especially electron density profiles and nuclear magnetic resonance (NMR) lipid order parameters (data not shown; as reported in [13,14]). Moreover, we are able to reproduce quite accurately the shape of the EPR resistance to permeation curves used to estimate permeability for POPC and POPC/cholesterol (Fig.1B).…”

“…The simulations used the Amber Lipid14 force field and cholesterol extension [13,14], along with the TIP3P explicit water model [15] and in-house O 2 parameters [12]. A tempocholine spin label moiety was modeled using Lipid14 force field atom types.…”

Magnification of Cholesterol-Induced Membrane Resistance on the Tissue Level: Implications for Hypoxia

“…All simulations used the GPU/CUDA-accelerated implementation [7] of the Amber 14 or Amber 12 biomolecular simulation software [8, 9], along with the Lipid14 force field [10] and a cholesterol extension by Ross Walker and Benjamin Madej [11]. We developed O 2 parameters in our laboratory, defining the bond length as 1.21 Å from the CRC Handbook [12], with a vibrational force constant of 849.16 kcal/mol • Å 2 based on Raman spectroscopic measurements [13] and with all other parameters defined the same as the carbonyl oxygen (oC) atom type in Lipid11 [14].…”

“…A bilayer containing 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and cholesterol in a 1:1 ratio was built with 128 lipids total, including 32 POPC and 32 cholesterol molecules per leaflet and was pre-equilibrated for 500 ns using the GAFFLipid force field [17] with the Lipid11 cholesterol parameters [14]. The Lipid14 force field [10] with a cholesterol extension by Ross Walker and Benjamin Madej [11] was used throughout the remaining simulations. The pre- equilibrated POPC/cholesterol system was further equilibrated for 200 ns with this force-field combination.…”

Computer simulations of protein–membrane systems

“…Lipid14, which works well with the tensionless NpT ensemble, can be combined with the AMBER FFs for proteins, nucleic acids, carbohydrates, 139 and small molecules, and was extended to mixed membranes including cholesterol. 140 There is also an update to the Lipid17 FF for anionic head groups and polyunsaturated acyl chains 141 ; however, it has not been applied yet, leaving it open how well it performs.…”