Validation of all-atom phosphatidylcholine lipid force fields in the tensionless NPT ensemble

Abstract

A recently defined charge set, to be used in conjunction with the all-atom CHARMM27r force field, has been validated for a series of phosphatidylcholine lipids. The work of Sonne et al. successfully replicated experimental bulk membrane behaviour for dipalmitoylphosphatidylcholine (DPPC) under the isothermal-isobaric (NPT) ensemble. Previous studies using the defined CHARMM27r charge set have resulted in lateral membrane contraction when used in the tensionless NPT ensemble, forcing the lipids to adopt a more ordered conformation than predicted experimentally. The current study has extended the newly defined charge set to 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) and 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylcholine (PDPC). Molecular dynamics simulations were run for each of the lipids (including DPPC) using both the CHARMM27r charge set and the newly defined modified charge set. In all three cases a significant improvement was seen in both bulk membrane properties and individual atomistic effects. Membrane width, area per lipid and the depth of water penetration were all seen to converge to experimental values. Deuterium order parameters generated with the new charge set showed increased disorder across the width of the bilayer and reflected both results from experiment and similar simulations run with united atom models. These newly validated models can now find use in mixed biological simulations under the tensionless ensemble without concern for lateral contraction.

Derivation and Systematic Validation of a Refined All-Atom Force Field for Phosphatidylcholine Lipids

“…Due the larger dipole moment in certain FFs, an angle of around 90° has been reported for lipid bilayer simulations, 23,47 wheres other reported values have been in within the range of 60–86°. 34,43,112−115 The torsional angles shown in Figure 1 (α 5 , α 4 , and α 3 ) are all in gauche conformations which agrees with the experimental findings of Akutsu and Nagamori. 111 This means that the intramolecular interactions in the lipid head group are described well and that its conformation is not fully extended.…”

“…A decrease in dipole moment reduces the attraction of the lipid head group with its neighbors in the membrane plane resulting in a more upright position. 43,110 In Figure 4, the probability distribution of the angle between the bilayer normal and the P–N vector is shown for DLPC, DMPC, and DPPC. The most probable angle is around 71° for all lipids compared to the experimental estimate of 72°.…”

Recent development in computer simulations of lipid bilayers

“…Very good agreement was also demonstrated for other experimentally measurable bilayer properties as bond order parameters, electron density and the structure factor 68 . In work 75 , simulations of bilayers composed of 16:0/16:0 PC, 16:0/18:1(n-9)cis PC and PDPC 16:0/22:6(n-3)cis PC lipids, with atomic charges derived in work 67 and with alkane torsion parameters described by c27r parameter set, also provided good agreement with experimental data for these types of lipids.…”

Intramolecular hydrogen bonding in articaine can be related to superior bone tissue penetration: A molecular dynamics study

“…Anisotropic pressure scaling was applied during constant pressure simulations, with a target of 1 bar in each dimension. Initial simulations under these conditions, without positional restraints, produced membranes that were too highly compressed (data not shown), as observed for similar systems in the literature [21,22,34,35,50]. Commonly employed approaches to circumvent this problem have been application of a constant positive surface tension to increase the lateral area of the membrane [19][20][21][22][23] or to keep the cross-sectional area of the bilayer fixed [27][28][29][30][31].…”

“…One such difficulty is to reproduce the area per lipid without either adding surface tension [19][20][21][22][23] or using constant volume [24][25][26] or fixed crosssectional area [27][28][29][30][31]. Nevertheless, experimentally validated areas per lipid have recently been achieved in tensionless constant pressure simulations of phosphatidylcholine bilayers with CHARMM [32][33][34] and GROMOS [35] force fields.…”