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Computer Simulations of Membrane–Sugar Interactions
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).ORCID iD: 0000-0003-3328-1921
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Carbohydrate molecules are essential parts of living cells. They are used as energy storage and signal substances, and they can be found incorporated in the cell membranes as attachments to glycoproteins and glycolipids, but also as free molecules. In this thesis the effect of carbohydrate molecules on phospholipid model membranes have been investigated by the means of Molecular Dynamics (MD) computer simulations.

The most abundant glycolipid in nature is the non-bilayer forming monogalactosyldiacylglycerol (MGDG). It is known to be important for the membrane stacking typical for the thylakoid membranes in plants, and has also been found essential for processes related to photosynthesis. In Paper I, MD simulations were used to characterize structural and dynamical changes in a lipid bilayer when MGDG is present. The simulations were validated by direct comparisons between dipolar couplings calculated from the MD trajectories, and those determined from NMR experiments on similar systems. We could show that most structural changes of the bilayer were a consequence of lipid packing and the molecular shape of MGDG.

In certain plants and organisms, the enrichment of small sugars such as sucrose and trehalose close to the membrane interfaces, are known to be one of the strategies to survive freezing and dehydration. The cryoprotecting abilities of these sugar molecules are long known, but the mechanisms at the molecular level are still debated. In Papers II–IV, the interactions of trehalose with a lipid bilayer were investigated. Calculations of structural and dynamical properties, together with free energy calculations, were used to characterize the effect of trehalose on bilayer properties. We could show that the binding of trehalose to the lipid bilayer follows a simple two state binding model, in agreement with recent experimental investigations, and confirm some of the proposed hypotheses for membrane–sugar interactions. The simulations were validated by dipolar couplings from our NMR investigations of TRH in a dilute liquid crystal (bicelles). Furthermore, the assumption about molecular structure being equal in the ordered and isotropic phases was tested and verified. This assumption is central for the interpretation of experimentally determined dipolar couplings in weakly ordered systems.

In addition, a coarse grain model was used to tackle some of the problems with slow dynamics that were encountered for trehalose in interaction with the bilayer. It was found that further developments of the interaction models are needed to properly describe the membrane–sugar interactions. Lastly, from investigations of trehalose curvature sensing, we concluded that it preferably interacts in bilayer regions with high negative curvature.

Place, publisher, year, edition, pages
Stockholm: Department of Materials and Environmental Chemistry (MMK), Stockholm University , 2016. , 78 p.
Keyword [en]
Molecular simulations, Molecular dynamics, Lipid bilayers, Carbohydrates, Biological membranes, Trehalose, Glycolipids, Membrane—sugar interactions
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-127402ISBN: 978-91-7649-363-2 (print)OAI: oai:DiVA.org:su-127402DiVA: diva2:909299
Public defence
2016-04-29, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2016-04-06 Created: 2016-03-03 Last updated: 2017-02-20Bibliographically approved
List of papers
1. Molecular Dynamics Simulations of Membranes Composed of Glycolipids and Phospholipids
Open this publication in new window or tab >>Molecular Dynamics Simulations of Membranes Composed of Glycolipids and Phospholipids
2012 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 1, 244-252 p.Article in journal (Refereed) Published
Abstract [en]

Lipid membranes composed of 1,2-di-(9Z,12Z,15Z)-octade-catrienoyl-3-O-β-D-galactosyl-sn-glycerol or monogalactosyldiacylglycerol(MGDG) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) were studied by means of molecular dynamics (MD) computer simulations. Three lipid compositions were considered: 0%, 20%, and 45% MGDG (by mole) denoted as MG-0, MG-20, and MG-45, respectively. The article is focused on the calculation of NMR dipolar interactions, which were confronted with previously reported experimental couplings. Dynamical processes and orientational distributions relevant for the averaging of dipolar interactions were evaluated. Furthermore, several parameters important for characterization of the bilayer structure, molecular organization, and dynamics were investigated. In general, only a minor change in DMPC properties was observed upon the increased MGDG/DMPC ratio, whereas properties related to MGDG undergo a more pronounced change. This effect was ascribed to the fact that DMPC is a bilayer (Lα) forming lipid, whereas MGDG prefers a reverse hexagonal (HII) arrangement.

Keyword
molecular dynamics, lyotropic liquid crystals, lipids, biomembranes, NMR parameters, dipolar couplings
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-69382 (URN)10.1021/jp209268p (DOI)000298978100031 ()
Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2017-12-08Bibliographically approved
2. Molecular Dynamics Simulations of Membrane-Sugar Interactions
Open this publication in new window or tab >>Molecular Dynamics Simulations of Membrane-Sugar Interactions
Show others...
2013 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, no 22, 6667-6673 p.Article in journal (Refereed) Published
Abstract [en]

It is well documented that disaccharides in general and trehalose (TRH) in particular strongly affect physical properties and functionality of lipid bilayers. We investigate interactions between lipid membranes formed by 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and TRH by means of molecular dynamics (MD) computer simulations. Ten different TRH concentrations were studied in the range W-TRH = 0-0.20 (w/w). The potential of mean force (PMF) for DMPC bilayer TRH interactions was determined using two different force fields, and was subsequently used in a simple analytical model for description of sugar binding at the membrane interface. The MD results were in good agreement with the predictions of the model. The net affinities of TRH for the DMPC bilayer derived from the model and MD simulations were compared with experimental results. The area per lipid increases and the membrane becomes thinner with increased TRH concentration, which is interpreted as an intercalation effect of the TRH molecules into the polar part of the lipids, resulting in conformational changes in the chains. These results are consistent with recent experimental observations. The compressibility modulus related to the fluctuations of the membrane increases dramatically with increased TRH concentration, which indicates higher order and rigidity of the bilayer. This is also reflected in a decrease (by a factor of 15) of the lateral diffusion of the lipids. We interpret these observations as a formation of a glassy state at the interface of the membrane, which has been suggested in the literature as a hypothesis for the membrane sugar interactions.

National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-92443 (URN)10.1021/jp402385d (DOI)000320215200009 ()
Funder
Swedish Research Council
Note

AuthorCount:6;

Available from: 2013-08-05 Created: 2013-08-05 Last updated: 2017-12-06Bibliographically approved
3. Molecular dynamics simulations and NMR spectroscopy studies of trehalose-lipid bilayer systems
Open this publication in new window or tab >>Molecular dynamics simulations and NMR spectroscopy studies of trehalose-lipid bilayer systems
Show others...
2015 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 34, 22438-22447 p.Article in journal (Refereed) Published
Abstract [en]

The disaccharide trehalose (TRH) strongly affects the physical properties of lipid bilayers. We investigate interactions between lipid membranes formed by 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and TRH using NMR spectroscopy and molecular dynamics (MD) computer simulations. We compare dipolar couplings derived from DMPC/TRH trajectories with those determined (i) experimentally in TRH using conventional high-resolution NMR in a weakly ordered solvent (bicelles), and (ii) by solid-state NMR in multilamellar vesicles (MLV) formed by DMPC. Analysis of the experimental and MD-derived couplings in DMPC indicated that the force field used in the simulations reasonably well describes the experimental results with the exception for the glycerol fragment that exhibits significant deviations. The signs of dipolar couplings, not available from the experiments on highly ordered systems, were determined from the trajectory analysis. The crucial step in the analysis of residual dipolar couplings (RDCs) in TRH determined in a bicelle-environment was access to the conformational distributions derived from the MD trajectory. Furthermore, the conformational behavior of TRH, investigated by J-couplings, in the ordered and isotropic phases is essentially identical, indicating that the general assumptions in the analyses of RDCs are well founded.

National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-120651 (URN)10.1039/c5cp02472b (DOI)000359971300074 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationCarl Tryggers foundation Swedish National Infrastructure for Computing (SNIC)
Available from: 2015-09-15 Created: 2015-09-15 Last updated: 2017-12-04Bibliographically approved
4. Coarse-Grained Molecular Dynamics Simulations of Membrane Trehalose Interactions
Open this publication in new window or tab >>Coarse-Grained Molecular Dynamics Simulations of Membrane Trehalose Interactions
2016 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, no 36, 9621-9631 p.Article in journal (Refereed) Published
Abstract [en]

It is well established that trehalose (TRH) affects the physical properties of lipid bilayers and stabilizes biological membranes. We present molecular dynamics (MD) computer simulations to investigate the interactions between lipid membranes formed by 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and TRH. Both atomistic and coarse-grained (CG) interaction models were employed, and the coarse graining of DMPC leads to a reduction in the acyl chain length corresponding to a 1,2-dilauroyl-sn-glycero-3-phosphocholine lipid (DLPC). Several modifications of the Martini interaction model, used for CG simulations, were implemented, resulting in different potentials of mean force (PMFs) for DMPC bilayer TRH interactions. These PMFs were subsequently used in a simple two-site analytical model for the description of sugar binding at the membrane interface. In contrast to that in atomistic MD simulations, the binding in the CG model was not in agreement with the two-site model. Our interpretation is that the interaction balance, involving water, TRH, and lipids, in the CG systems needs further tuning of the force-field parameters. The area per lipid is only weakly affected by TRH concentration, whereas the compressibility modulus related to the fluctuations of the membrane increases with an increase in TRH content. In agreement with experimental findings, the bending modulus is not affected by the inclusion of TRH. The important aspects of lipid bilayer interactions with biomolecules are membrane curvature generation and sensing. In the present investigation, membrane curvature is generated by artificial buckling of the bilayer in one dimension. It turns out that TRH prefers the regions with the highest curvature, which enables the most favorable situation for lipid sugar interactions.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-135184 (URN)10.1021/acs.jpcb.6b06566 (DOI)000383641300008 ()27530142 (PubMedID)
Available from: 2016-11-17 Created: 2016-11-01 Last updated: 2017-11-29Bibliographically approved

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