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Extension of the Slipids Force Field to Polyunsaturated Lipids Inna Ermilova and Alexander P

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Extension of the Slipids Force Field to Polyunsaturated Lipids Inna Ermilova and Alexander P Article pubs.acs.org/JPCB Extension of the Slipids Force Field to Polyunsaturated Lipids Inna Ermilova and Alexander P. Lyubartsev* Department of Materials and Environmental Chemistry, Stockholm University, SE 106 91 Stockholm, Sweden *S Supporting Information ABSTRACT: The all-atomic force field Slipids (Stockholm Lipids) for lipid bilayers simulations has been extended to polyunsaturated lipids. Following the strategy adopted in the development of previous versions of the Slipids force field, the parametrization was essentially based on high-level ab initio calculations. Atomic charges and torsion angles related to polyunsaturated lipid tails were parametrized using structures of dienes molecules. The new parameters of the force field were validated in simulations of bilayers composed of seven polyunsaturated lipids. An overall good agreement was found with available experimental data on the areas per lipids, volumetric properties of bilayers, deuterium order parameters, and scattering form factors. Furthermore, simulations of bilayers consisting of highly polyunsaturated lipids and cholesterol molecules have been carried out. The majority of cholesterol molecules were found in a position parallel to bilayer normal with the hydroxyl group directed to the membrane surface, while a small fraction of cholesterol was found in the bilayer center parallel to the membrane plane. Furthermore, a tendency of cholesterol molecules to form chain-like clusters in polyunsaturated bilayers was qualitatively observed. ■ INTRODUCTION docosahexaenoic acid is not only affecting physical-chemical properties of membranes (such as thickness, lipid packing, Lipids are important components of biological systems, such as fl biomembranes.1,2 A lipid bilayer forming a membrane helps to uidity, elasticity, permeability, etc.), but it is activating the control the transport of different molecules into or out of a important signaling protein kinase C (PKC) as well. The 3,4 activity of this protein was higher in a failed human heart cell. Furthermore, the membrane itself is involved in many 38 important processes, such as cell division, cell signaling, protein compared to a healthy one according to Bowling et al. The fact that PUFA lipids affect so wide variety of biological anchoring, cell fusion, which are happening on a microscopic fi level.5,6 Lipids composed of polyunsaturated fatty acids processes is evidently linked to their speci c chemical structure with methylene-interrupted cis double bonds, which causes (PUFAs) are very common in mammalian cells including fi 39 humans.7,8 In particular, they are highly abundant in the eye their speci c functioning in living organisms. Molecular dynamics (MD) simulations can provide valuable retina and in the brain gray and white matter as one of the side fi chains of phosphatidylethanolamine (PE) and phosphatidylser- information for understanding of speci c features of PUFA ine (PS).7 In addition, linoelic acid is a dominant substituent of lipids, and through the years a number of works on atomistic 7 fl simulations of bilayers composed of PUFA lipids have been cardiolipin, which is found in the heart and in the inner lea et 40−48 of mitochondrial membranes. The amount of PUFAs in carried out. Still, the amount of modeling studies on different cells plays a big role in the human’s health. Some PUFA is much less than what is available for fully saturated nutritionists suggest consumption of products which are rich lipids. Partially this can be related to the lack of reliable with ω-3 and ω-6 fatty acids in order to avoid issues with the parametrization of the interactions in the polyunsaturated health9 (the terms ω-3 and ω-6 mean polyunsaturated fatty hydrocarbon chains. Reliability of results obtained by MD fi simulations depends crucially on the force field (FF) used. In acids which have the rst double bond C C at the third or fi sixth carbon atom from the end of the chain, respectively). It order to get reliable results the force eld should accurately was also discovered that PUFAs are useful for the treatment of describe all interactions in the system of interest. − mental diseases and memory problems,10 19 heart diseases and For lipid bilayers, there is a relatively large variety of force − fi problems with a high blood pressure,20 25 atherosclerosis, elds. Often MD simulations of lipid bilayers are carried out fl 26 27−30 31 using united atom Gromos FF and its variations: Berger dyslipidemia, in ammation, cancer, Parkinson, prob- 49 50 lems with the vision,32 diabetes, and fatty liver disease.33,34 The lipids, 43A1-S3 FF parameter set, or G53A6L parameter 51 fi significant positive effects of the consumption of PUFAs were set. Use of united-atom force elds is less suitable for discovered on children’s performance inlearning.35 At the same modeling of unsaturated lipids because of a weak polarity at the time some harmful effects of the consumption of PUFAs were discovered: pro-hemorrhagic effect, negative effects on immune Received: May 30, 2016 functions, formation of oxidative products by ω-3 polyunsatu- Revised: November 30, 2016 rated fatty acids.36 Stillwell et al.37 have shown that Published: November 30, 2016 © 2016 American Chemical Society 12826 DOI: 10.1021/acs.jpcb.6b05422 J. Phys. Chem. B 2016, 120, 12826−12842 The Journal of Physical Chemistry B Article double bonds which is not included into united atom FFs ■ METHODS AND MODELS having zero charges of united atom groups. There are also all- Parametrization Strategy. In this work we have focused atomistic FFs with all hydrogens explicitly included, which were on the polyunsaturated tails of lipid molecules having repeated developed for modeling of lipids: several versions of − methylene-separated cis double bonds. Parameters for the lipid CHARMM,52 55 AMBER family (GAFF, lipid11, − − headgroups and saturated parts of the lipid tails are kept as in 56 59 60 61 63 − lipid14), GLYCAM06, Slipids, see also recent the previous versions of the Slipids FF,61 63 in which bond, 64 fi review and references therein. All these force elds contain angular, Urey−Bradley, and a part of Lennard-Jones parameters parameters for a double C C cis bond, however they were were inherited from the Charmm36 FF.55 derived and validated for an isolated double bond which, for This FF has a standard molecular mechanics form: example, is present in such lipids as DOPC or POPC. However, application of parameters derived for a single double bond to Uff=+++++EEEEEE bonds angles U−‐ B tors L J electrostatic polyunsaturated lipids having several methylene-separated cis (1) double bonds often leads to inaccurate descriptions of the Particularly in this work we reparametrized electrostatic surface area per lipid, deuterium order parameters, and X-ray E and torsional E parts of the FF which have 65 electrostaic tors form factors. To our knowledge, the only atomistic force field strongest effect on the conformational behavior of lipids and which includes parameters specially developed for PUFA chains their interaction with other molecules. The electrostatic fi 65 is a recent modi cation of Charmm36 which was made by interactions are determined by the partial charges qi of atoms: adjustment of the torsion potential between two methylene- qqij separated cis double bonds. Apart from that, there exists a E = ∑ united atom model based on Berger force field66 and a coarse- electrostatic 4πϵ r i,j 0ij (2) grained model based on MARTINI force field67 which include special parameters for PUFA chains. while the torsional potential is presented by a cosine expansion In this work we extend the Slipids force field to up to the 6-th term: polyunsaturated lipids. The original all-atomistic Slipids 6 61−63 FF was derived for saturated and monounsaturated lipids Ek=+−∑ (1 cos( nϕδ )) ff tors nn with a number of di erent headgroups and validated by n=1 (3) comparisons of computed properties of lipid bilayers with available experimental data: average areas per lipid, bilayer The Lennard-Jones and electrostatic interactions are not thickness, X-ray and neutron scattering form factors, NMR computed for atoms pairs connected by 1 or 2 covalent fi bonds. For atom pairs connected by exactly 3 bonds (the so- deuterium order parameters. Slipids force eld demonstrates − also a good description of the temperature dependencies of called 1 4 neighbors), special rules are applied. In the case of Slipids FF, 1−4 electrostatic interactions are scaled by factor experimentally observed bilayer properties including transition fi to the gel phase, and partitioning of various molecular 0.83, while special rules (de ned by the FF atom types) are − − 61 inclusions across the bilayer.68 70 In the extension of Slipids applied for 1 4 Lennard-Jones interactions. to polyunsaturated lipids we adopt the methodology used in the To optimize FF parameters for atom types related to − previous works61 63 based on high-level ab initio computations repeated cis double bonds we used two model molecules: cis- of partial charges with multiconfigurational averaging, and 3,cis-6-nonadiene and cis-3,cis-6-dodecadiene (Figure S1 and S2 subsequent parametrization of the torsion potentials. of the Supporting Information). The parametrization algorithm The developed force field is validated by simulations of involves several steps: several phosphatidylcholine (PC) lipids containing different 1. We run a MD simulation of model molecules in a liquid numbers of double bonds in unsaturated tails: 18:1(n−9), phase and extract from it randomly 50 molecular 18:2(n−9), 18:3(n−3), 20:4(n−6), 20:5(n−3), 22:5(n−6), conformations. 22:6(n−3), and comparisons with available experimental data. 2. For the chosen conformations we compute partial atomic Here and below we use numerical notations for the charges and for each atom type take average over the phospholipid chains in the form N:k(n−j) where N denotes conformations.
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