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Modeling of biomembranes: from computational toxicology to simulations of neurodegenerative diseases
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK). (Lyubartsev)ORCID-id: 0000-0001-7371-8644
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Materials and Environmental Chemistry, Stockholm University , 2019. , s. 90
Nyckelord [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
Nationell ämneskategori
Fysikalisk kemi
Forskningsämne
fysikalisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-165940ISBN: 978-91-7797-584-7 (tryckt)ISBN: 978-91-7797-585-4 (digital)OAI: oai:DiVA.org:su-165940DiVA, id: diva2:1286858
Disputation
2019-03-27, Magnélisalen Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Submitted.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

Tillgänglig från: 2019-03-04 Skapad: 2019-02-08 Senast uppdaterad: 2019-02-25Bibliografiskt granskad
Delarbeten
1. Extension of the Slipids Force Field to Polyunsaturated Lipids
Öppna denna publikation i ny flik eller fönster >>Extension of the Slipids Force Field to Polyunsaturated Lipids
2016 (Engelska)Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, nr 50, s. 12826-12842Artikel i tidskrift (Refereegranskat) 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.

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Identifikatorer
urn:nbn:se:su:diva-139387 (URN)10.1021/acs.jpcb.6b05422 (DOI)000390735800005 ()
Tillgänglig från: 2017-02-07 Skapad: 2017-02-06 Senast uppdaterad: 2019-02-11Bibliografiskt granskad
2. Quantum chemical and molecular dynamics modelling of hydroxylated polybrominated diphenyl ethers
Öppna denna publikation i ny flik eller fönster >>Quantum chemical and molecular dynamics modelling of hydroxylated polybrominated diphenyl ethers
2017 (Engelska)Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, nr 41, s. 28263-28274Artikel i tidskrift (Refereegranskat) 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.

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urn:nbn:se:su:diva-148826 (URN)10.1039/c7cp03471g (DOI)000413778800039 ()29028067 (PubMedID)
Tillgänglig från: 2017-11-14 Skapad: 2017-11-14 Senast uppdaterad: 2019-02-11Bibliografiskt granskad
3. Cholesterol in phospholipid bilayers: positions and orientations inside membranes with different unsaturation degrees
Öppna denna publikation i ny flik eller fönster >>Cholesterol in phospholipid bilayers: positions and orientations inside membranes with different unsaturation degrees
2019 (Engelska)Ingår i: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 15, nr 1, s. 78-93Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Fysikalisk kemi
Forskningsämne
fysikalisk kemi
Identifikatorer
urn:nbn:se:su:diva-165616 (URN)10.1039/C8SM01937A (DOI)000454838800007 ()
Tillgänglig från: 2019-02-03 Skapad: 2019-02-03 Senast uppdaterad: 2019-02-08Bibliografiskt granskad
4. Effects of lipid saturation on amyloid-beta peptides partitioning and aggregation in neuronal membranes: molecular dynamics simulations
Öppna denna publikation i ny flik eller fönster >>Effects of lipid saturation on amyloid-beta peptides partitioning and aggregation in neuronal membranes: molecular dynamics simulations
2019 (Engelska)Ingår i: European Biophysics Journal, ISSN 0175-7571Artikel i tidskrift (Refereegranskat) Submitted
Nationell ämneskategori
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fysikalisk kemi
Identifikatorer
urn:nbn:se:su:diva-165902 (URN)
Tillgänglig från: 2019-02-06 Skapad: 2019-02-06 Senast uppdaterad: 2019-02-11Bibliografiskt granskad
5. Modelling of interactions between Aβ(25-35) peptide and phospholipid bilayers: effects of cholesterol and lipid saturation
Öppna denna publikation i ny flik eller fönster >>Modelling of interactions between Aβ(25-35) peptide and phospholipid bilayers: effects of cholesterol and lipid saturation
2019 (Engelska)Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084Artikel i tidskrift (Refereegranskat) Submitted
Nationell ämneskategori
Fysikalisk kemi
Forskningsämne
fysikalisk kemi
Identifikatorer
urn:nbn:se:su:diva-165903 (URN)
Tillgänglig från: 2019-02-06 Skapad: 2019-02-06 Senast uppdaterad: 2019-02-11Bibliografiskt granskad

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