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Quantum Chemical Modeling of the Cardiolipin Headgroup
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
Department of Chemistry, University of Pisa.
Department of Chemistry, University of Pisa.
2010 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 114, no 12, 4375-4387 p.Article in journal (Refereed) Published
Abstract [en]

Cardiolipin is a key lipid component in many biological membranes. Proton conduction and proton−lipid interactions on the membrane surface are thought to be central to mitochondrial energy production. However, details on the cardiolipin headgroup structure are lacking and the protonation state of this lipid at physiological pH is not fully established. Here we present ab initio DFT calculations of the cardiolipin (CL) headgroup and its 2′-deoxy derivative (dCL), with the aim of establishing a connection between structure and acid−base equilibrium in CL. Furthermore, we investigate the effects of solvation on the molecular conformations. In our model, both CL and dCL showed a significant gap between the two pKa values, with pKa2 above the physiological range, and intramolecular hydrogen bonds were found to play a central role in the conformations of both molecules. This behavior was also observed experimentally in CL. Structures derived from the DFT calculations were compared with those obtained experimentally, collected for CL in the Protein Data Bank, and conformations from previous as well as new molecular dynamics simulations of cardiolipin bilayers. Transition states for proton transfer in CL were investigated, and we estimate that protons can exchange between phosphate groups with an approximate 4−5 kcal/mol barrier. Computed NMR and IR spectral properties were found to be in reasonable agreement with experimental results available in the literature.

Place, publisher, year, edition, pages
2010. Vol. 114, no 12, 4375-4387 p.
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-37611DOI: 10.1021/jp9110019ISI: 000275855500044OAI: oai:DiVA.org:su-37611DiVA: diva2:304018
Projects
Liquid Crystals and Membrane Models
Available from: 2010-03-16 Created: 2010-03-16 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Molecular Modeling of Cardiolipin
Open this publication in new window or tab >>Molecular Modeling of Cardiolipin
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biological membranes are assembled from many different lipids. Our understanding of membrane function and morphology is dependent on linking the properties of the lipids to the properties of the membranes. In the inner mitochondrial membrane, one of the main lipids is cardiolipin, which is involved in the formation of high curvature tubular regions. In this thesis a series of molecular models of cardiolipin is presented, with the aim of providing a bottom-up understanding for its influence on model and biological membranes. The models allow detailed control over the headgroup charge and the chain volumes, which experimentally have shown to be important for the packing, mechanical, and electrostatic properties of membranes.To achieve these aims, three levels of detail were used: i) quantum chemical calculations for the cardiolipin headgroup, ii) atomistic united atom molecular dynamics simulations for cardiolipin and phosphatidylcholine lipid mixtures, and iii) coarse grained molecular dynamics simulations for larger lipid systems, including phase transitions between the micellar, lamellar, and inverse hexagonal phases, as well as mixtures of cardiolipin with zwitterionic lipids. These models are presented in the context of various experiments on cardiolipin systems done by others, and some basic theory of electrostatics and mechanics of membranes are discussed.The simple coarse grained model gave lipid phase preferences in agreement with experimental data. Relatively small amounts of partially neutralized cardiolipin molecules introduced mechanical instability in phosphatidylcholine bilayers, and showed some evidence of domain formation due to curvature frustration. The small effective headgroup volume of cardiolipin induced order in the hydrocarbon chains, partly due to strong sodium ion binding. Different types of intramolecular hydrogen bond networks in cardiolipin were described, and proton transfer between the phosphate groups within a cardiolipin molecule was estimated to have a 4-5 kcal/mol barrier. Such transfer might play a role in the surface conduction of protons at the inner mitochondrial membrane.

Place, publisher, year, edition, pages
Stockholm: Department of Materials and Environmental Chemistry (MMK), Stockholm University, 2010. 97 p.
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-37613 (URN)978-91-7447-024-6 (ISBN)
Public defence
2010-04-16, Magnelisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Submitted.Available from: 2010-03-25 Created: 2010-03-16 Last updated: 2010-03-17Bibliographically approved

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