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Modeling of biomembranes: from computational toxicology to simulations of neurodegenerative diseases
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). (Lyubartsev)ORCID iD: 0000-0001-7371-8644
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It was known from the middle of the last century that a cell-membrane is a lipid bilayer. Since that time a large number of experimental studies has been done in order to see how a certain molecule can penetrate through a membrane. Due to the complexity of laboratory experiments computational chemistry became a convenient tool for investigations involving this process. In a real life a compound has to pass through several membranes of different chemical composition before reaching the actual target. Such a diversity in constitution gives a various selectivity to cell-membranes: some molecules will penetrate through them and others will not. That is why the development and a choice of suitable models for lipid bilayers are important steps in such a research. In this thesis new all-atomistic models for polyunsaturated phospholipids in cis conformations have been derived and added to the SLipids force field. After a successful force field validation, the new lipid models were used in molecular dynamics and well-tempered metadynamics simulations of several problems, such as toxicity of hydroxylated polybrominated diphenyl ethers (OH-PBDE), behavior of cholesterol in various membranes, an aggregation of amyloid-β (Aβ) peptides. The significance of the presence of lipid unsaturation has been demonstrated by all computations. 2’-OH-BDE68 (ortho) showed the affinity to saturated lipid bilayer, but had more conformational variations in the center of the unsaturated membrane. Cholesterol did not exhibit the preference to polynsaturated lipid bilayers from free energy calculations, but the diversity in orientations of this molecule, depending on its locations was observed. The behavior of Aβ peptides was dependent on membrane saturation as well. The insertion of Aβ peptides was detected in lipid bilayers containing higher amounts of polyunsaturated phospholipids, while in systems with more saturated membranes amyloids aggregated on membrane surfaces. Moreover, a comparison of simulations for quadro- and mono-component lipid bilayers showed that the membrane built of 18:0-22:6 PC can serve as a good model for the ’healthy’ tissue of a human brain. Also the lipid bilayer built of 14:0-14:0 PC exhibited similar features as the quadro-lipid membrane representing the brain tissue affected by Alzheimer’s disease. Good agreement of some computational results with available experimental findings demonstrated the applicability of computer simulations to real life problems.

Place, publisher, year, edition, pages
Stockholm: Department of Materials and Environmental Chemistry, Stockholm University , 2019. , p. 90
Keywords [en]
biomembranes, lipid bilayers, Alzheimer's disease, Parkinson disease, computational toxicology, passive diffusion, hydroxylated polybrominated diphenyl ethers, omega-3, omega-6, amyloid beta peptide, molecular dynamics simulations, SLipids force field
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-165940ISBN: 978-91-7797-584-7 (print)ISBN: 978-91-7797-585-4 (electronic)OAI: oai:DiVA.org:su-165940DiVA, id: diva2:1286858
Public defence
2019-03-27, Magnélisalen Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Submitted. Paper 5: Submitted.

Available from: 2019-03-04 Created: 2019-02-08 Last updated: 2019-02-25Bibliographically approved
List of papers
1. Extension of the Slipids Force Field to Polyunsaturated Lipids
Open this publication in new window or tab >>Extension of the Slipids Force Field to Polyunsaturated Lipids
2016 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, no 50, p. 12826-12842Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Chemical Sciences
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-139387 (URN)10.1021/acs.jpcb.6b05422 (DOI)000390735800005 ()
Available from: 2017-02-07 Created: 2017-02-06 Last updated: 2019-02-11Bibliographically approved
2. Quantum chemical and molecular dynamics modelling of hydroxylated polybrominated diphenyl ethers
Open this publication in new window or tab >>Quantum chemical and molecular dynamics modelling of hydroxylated polybrominated diphenyl ethers
2017 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, no 41, p. 28263-28274Article in journal (Refereed) Published
Abstract [en]

A series of 19 hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been studied using density functional theory (DFT) and molecular dynamics simulations with the purpose of investigating eventual correlations between their physicochemical properties and toxic action. Dissociation constants (pK(a)), solvation free energies and octanol-water partition coefficients (logP) have been computed. Additionally, metadynamics simulations of OH-PBDEs passing through a lipid bilayer have been carried out for four OH-PBDE species. No correlations between computed pKa values and toxicity data have been found. Medium correlations were found between partition coefficients and the ability of OH-PBDEs to alter membrane potential in cell cultures, which is attributed to higher uptake of molecules with larger log P parameters. It was also demonstrated that in lipid bilayers, OH-PBDE molecules differ in their orientational distributions and can adopt different conformations which can affect the uptake of these molecules and influence the pathways of their toxic action.

National Category
Chemical Sciences
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-148826 (URN)10.1039/c7cp03471g (DOI)000413778800039 ()29028067 (PubMedID)
Available from: 2017-11-14 Created: 2017-11-14 Last updated: 2019-02-11Bibliographically approved
3. Cholesterol in phospholipid bilayers: positions and orientations inside membranes with different unsaturation degrees
Open this publication in new window or tab >>Cholesterol in phospholipid bilayers: positions and orientations inside membranes with different unsaturation degrees
2019 (English)In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 15, no 1, p. 78-93Article in journal (Refereed) Published
Abstract [en]

Cholesterol is an essential component of all animal cell membranes and plays an important role in maintaining the membrane structure and physical–chemical properties necessary for correct cell functioning. The presence of cholesterol is believed to be responsible for domain formation (lipid rafts) due to different interactions of cholesterol with saturated and unsaturated lipids. In order to get detailed atomistic insight into the behaviour of cholesterol in bilayers composed of lipids with varying degrees of unsaturation, we have carried out a series of molecular dynamics simulations of saturated and polyunsaturated lipid bilayers with different contents of cholesterol, as well as well-tempered metadynamics simulations with a single cholesterol molecule in these bilayers. From these simulations we have determined distributions of cholesterol across the bilayer, its orientational properties, free energy profiles, and specific interactions of molecular groups able to form hydrogen bonds. Both molecular dynamics and metadynamics simulations showed that the most unsaturated bilayer with 22:6 fatty acid chains shows behaviour which is most different from other lipids. In this bilayer, cholesterol is relatively often found in a “flipped” configuration with the hydroxyl group oriented towards the membrane middle plane. This bilayer has also the highest (least negative) binding free energy among liquid phase bilayers, and the lowest reorientation barrier. Furthermore, cholesterol molecules in this bilayer are often found to form head-to-tail contacts which may lead to specific clustering behaviour. Overall, our simulations support ideas that there can be a subtle interconnection between the contents of highly unsaturated fatty acids and cholesterol, deficiency or excess of each of them is related to many human afflictions and diseases.

National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-165616 (URN)10.1039/C8SM01937A (DOI)000454838800007 ()
Available from: 2019-02-03 Created: 2019-02-03 Last updated: 2019-02-08Bibliographically approved
4. Effects of lipid saturation on amyloid-beta peptides partitioning and aggregation in neuronal membranes: molecular dynamics simulations
Open this publication in new window or tab >>Effects of lipid saturation on amyloid-beta peptides partitioning and aggregation in neuronal membranes: molecular dynamics simulations
2019 (English)In: European Biophysics Journal, ISSN 0175-7571Article in journal (Refereed) Submitted
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-165902 (URN)
Available from: 2019-02-06 Created: 2019-02-06 Last updated: 2019-02-11Bibliographically approved
5. Modelling of interactions between Aβ(25-35) peptide and phospholipid bilayers: effects of cholesterol and lipid saturation
Open this publication in new window or tab >>Modelling of interactions between Aβ(25-35) peptide and phospholipid bilayers: effects of cholesterol and lipid saturation
2019 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084Article in journal (Refereed) Submitted
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-165903 (URN)
Available from: 2019-02-06 Created: 2019-02-06 Last updated: 2019-02-11Bibliographically approved

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