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  • 1.
    Lundborg, Magnus
    et al.
    ERCO Pharma AB, Sci Life Lab, Solna, Sweden..
    Narangifard, Ali
    ERCO Pharma AB, Sci Life Lab, Solna, Sweden.;Karolinska Inst, Dept Med, Solna MedS, Solna, Sweden..
    Wennberg, Christian L.
    KTH, School of Engineering Sciences (SCI), Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre. ERCO Pharma AB, Sci Life Lab, Solna, Sweden..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
    Daneholt, Bertil
    Karolinska Inst, Dept Cell & Mol Biol CMB, Stockholm, Sweden..
    Norlén, Lars
    Karolinska Inst, Dept Cell & Mol Biol CMB, Stockholm, Sweden.;Karolinska Univ Hosp, Dermatol Clin, Stockholm, Sweden..
    Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation2018In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 203, no 2, p. 149-161Article in journal (Refereed)
    Abstract [en]

    In the present study we have analyzed the molecular structure and function of the human skin's permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin. The skin's barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin - the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure's detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial. Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models' lipid composition was to that reported in human stratum corneum, the better was the match between the models' simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model's calculated water permeability and thermotropic behaviour were found compatible with that of human skin. The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems.

  • 2.
    Narangifard, A.
    et al.
    KI, Dept Med, Solna MedS, Stockholm, Sweden.;ERCO Pharma AB, Sci Life Lab, Stockholm, Sweden..
    den Hollander, L.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden..
    Wennberg, Christian L.
    KTH, School of Engineering Sciences (SCI), Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundborg, M.
    ERCO Pharma AB, Sci Life Lab, Stockholm, Sweden..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Iwai, I.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden..
    Han, H.
    Max Planck Inst Mol Physiol, Syst Cell Biol, Dortmund, Germany..
    Masich, S.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden..
    Daneholt, B.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden..
    Norlen, L.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dermatol Clin, Stockholm, Sweden..
    Human skin barrier formation takes place via a cubic to lamellar lipid phase transition as analyzed by cryo-electron microscopy and EM-simulation2018In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 366, no 2, p. 139-151Article in journal (Refereed)
    Abstract [en]

    The skin's permeability barrier consists of stacked lipid sheets of splayed ceramides, cholesterol and free fatty acids, positioned intercellularly in the stratum corneum. We report here on the early stage of skin barrier formation taking place inside the tubuloreticular system in the secretory cells of the topmost viable epidermis and in the intercellular space between viable epidermis and stratum corneum. The barrier formation process was analysed in situ in its near-native state, using cryo-EM combined with molecular dynamics modeling and EM simulation. Stacks of lamellae appear towards the periphery of the tubuloreticular system and they are closely associated with granular regions. Only models based on a bicontinuous cubic phase organization proved compatible with the granular cryo-EM patterns. Only models based on a dehydrated lamellar phase organization agreed with the lamellar cryo-EM patterns. The data support that human skin barrier formation takes place via a cubic to lamellar lipid phase transition.

  • 3.
    Wennberg, Christian
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Computational modeling of biological barriers2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One of the most important aspects for all life on this planet is the act to keep their biological processes in a state where they do not reach equilibrium. One part in the upholding of this imbalanced state is the barrier between the cells and their surroundings, created by the cell membrane. Additionally, terrestrial animal life often requires a barrier that protects the organism's body from external hazards and water loss. As an alternative to experiments, the investigation of the processes occurring at these barriers can be performed by using molecular dynamics simulations. Through this method we can obtain an atomistic description of the dynamics associated with events that are not accessible to experimental setups.

     In this thesis the first paper presents an improved particle-mesh Ewald method for the calculation of long-range Lennard-Jones interactions in molecular dynamics simulations, which solves the historical performance problem of the method. The second paper demonstrate an improved implementation, with a higher accuracy, that only incurs a performance loss of roughly 15% compared to conventional simulations using the Gromacs simulation package. Furthermore, the third paper presents a study of cholesterol's effect on the permeation of six different solutes across a variety of lipid bilayers. A laterally inhomogeneous permeability in cholesterol-containing membranes is proposed as an explanation for the large differences between experimental permeabilities and calculated partition coefficients in simulations. The fourth paper contains a coarse-grained simulation study of a proposed structural transformation in ceramide bilayer structures, during the formation of the stratum corneum. The simulations show that glycosylceramides are able to stabilize a three-dimensionally folded bilayer structure, while simulations with ceramides collapse into a lamellar bilayer structure.

  • 4.
    Wennberg, Christian L.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Exploring the Interactive Landscape of Lipid Bilayers2014Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    One of the most important aspects for all life on this planet is theact to keep their cellular processes in a state where they do notreach equilibrium. One part in the upholding of this imbalanced stateis the barrier between the cells and their surroundings, created bythe cell membrane. In addition to experiments, the investigation ofprocesses occuring in the cell membrane can be performed by usingmolecular dynamics simulations. Through this method we can obtain anatomistic description of the dynamics associated with events that arenot accessible to experimental setups. Molecular dynamics relies onthe integration of Newton's equations of motion in order to sample therelevant parts of phase-space for the system, and therefore it isdependent on a correct description of the interactions between all thesimulated particles. In this thesis I first present an improved methodfor the calculation of long-range interactions in molecular dynamicssimulations, followed by a study of cholesterol's impact on thepermeation of small solutes across a lipid bilayer.

    The first paper presents a previously derived modification to theparticle-mesh Ewald method, which makes it possible to apply thisto long-range Lennard-Jones interactions. Old implementations of themethod have been haunted by an extreme performance degradation andhere I propose a solution to this problem by applying a modifiedinteraction potential. I further show that the historical treatmentof long-range interactions in simulations of lipid bilayers hasnon-negligible effects on their structural properties.In the second paper, this modification is improved such that the smallerrors introduced by the modified interaction potential becomenegligible. Furthermore, I demonstrate that I have also improved theimplementation of the method so that it now only incurs a performanceloss of roughly 15% compared to conventional simulations using theGromacs simulation package.The third paper presents a simulation study of cholesterol's effect onthe permeation of six different solutes across a variety of lipidbilayers. I analyze the effect of different head groups, tail lengths,and tail saturation by performing simulations of the solutes in fourdifferent bilayers, with cholesterol contents between 0% and50%. Analysis of the simulations shows that the impact of the surfacearea per lipid on the partitioning of the solute could be lower thanpreviously thought. Furthermore, a model with a laterallyinhomogeneous permeability in cholesterol-containing membranes isproposed, which could explain the large differences betweenpermeabilities from experiments and calculated partition coefficientsin simulations.

  • 5.
    Wennberg, Christian L.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Murtola, Teemu
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Improved Accuracy and Performance of Lennard-Jones Lattice Summation in GromacsManuscript (preprint) (Other academic)
  • 6.
    Wennberg, Christian L.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Murtola, Teemu
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lennard-Jones Lattice Summation in Bilayer Simulations Has Critical Effects on Surface Tension and Lipid Properties2013In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 9, no 8, p. 3527-3537Article in journal (Refereed)
    Abstract [en]

    The accuracy of electrostatic interactions in molecular dynamics advanced tremendously with the introduction of particle-mesh Ewald (PME) summation almost 20 years ago. Lattice summation electrostatics is now the de facto standard for most types of biomolecular simulations, and in particular, for lipid bilayers, it has been a critical improvement due to the large charges typically present in zwitterionic lipid headgroups. In contrast, Lennard-Jones interactions have continued to be handled with increasingly longer cutoffs, partly because few alternatives have been available despite significant difficulties in tuning cutoffs and parameters to reproduce lipid properties. Here, we present a new Lennard-Jones PME implementation applied to lipid bilayers. We confirm that long-range contributions are well approximated by dispersion corrections in simple systems such as pentadecane (which makes parameters transferable), but for inhomogeneous and anisotropic systems such as lipid bilayers there are large effects on surface tension, resulting in up to 5.5% deviations in area per lipid and order parameters-far larger than many differences for which reparameterization has been attempted. We further propose an approximation for combination rules in reciprocal space that significantly reduces the computational cost of Lennard-Jones PME and makes accurate treatment of all nonbonded interactions competitive with simulations employing long cutoffs. These results could potentially have broad impact on important applications such as membrane proteins and free energy calculations.

  • 7.
    Wennberg, Christian L.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Murtola, Teemu
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Pall, Szilard
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Abraham, Mark James
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Hess, Berk
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Direct-Space Corrections Enable Fast and Accurate Lorentz-Berthelot Combination Rule Lennard-Jones Lattice Summation2015In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 11, no 12, p. 5737-5746Article in journal (Refereed)
    Abstract [en]

    Long-range lattice summation techniques such as the particle-mesh Ewald (PME) algorithm for electrostatics have been revolutionary to the precision and accuracy of molecular simulations in general. Despite the performance penalty associated with lattice summation electrostatics, few biomolecular simulations today are performed without it. There are increasingly strong arguments for moving in the same direction for Lennard-Jones (LJ) interactions, and by using geometric approximations of the combination rules in reciprocal space, we have been able to make a very high-performance implementation available in GROMACS. Here, we present a new way to correct for these approximations to achieve exact treatment of Lorentz-Berthelot combination rules within the cutoff, and only a very small approximation error remains outside the cutoff (a part that would be completely ignored without LJ-PME). This not only improves accuracy by almost an order of magnitude but also achieves absolute biomolecular simulation performance that is an order of magnitude faster than any other available lattice summation technique for LJ interactions. The implementation includes both CPU and GPU acceleration, and its combination with improved scaling LJ-PME simulations now provides performance close to the truncated potential methods in GROMACS but with much higher accuracy.

  • 8.
    Wennberg, Christian L.
    et al.
    Uppsala University, Sweden.
    van der Spoel, David
    Hub, Jochen S.
    Large Influence of Cholesterol on Solute Partitioning into Lipid Membranes2012In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 11, p. 5351-5361Article in journal (Refereed)
    Abstract [en]

    Cholesterol plays an important role in maintaining the correct fluidity and rigidity of the plasma membrane of all animal cells, and hence, it is present in concentrations ranging from 20 to 50 mol %. Whereas the effect of cholesterol on such mechanical properties has been studied exhaustively over the last decades, the structural basis for cholesterol effects on membrane permeability is still unclear. Here we apply systematic molecular dynamics simulations to study the partitioning of solutes between water and membranes. We derive potentials of mean force for six different solutes permeating across 20 different lipid membranes containing one out of four types of phospholipids plus a cholesterol content varying from 0 to 50 mol %. Surprisingly, cholesterol decreases solute partitioning into the lipid tail region of the membranes much more strongly than expected from experiments on macroscopic membranes, suggesting that a laterally inhomogeneous cholesterol concentration and permeability may be required to explain experimental findings. The simulations indicate that the cost of breaking van der Waals interactions between the lipid tails of cholesterol-containing membranes account for the reduced partitioning rather than the surface area per phospholipid, which has been frequently suggested as a determinant for solute partitioning. The simulations further show that the partitioning is more sensitive to cholesterol (i) for larger solutes, (ii) in membranes with saturated as compared to membranes with unsaturated lipid tails, and (iii) in membranes with smaller lipid head groups.

  • 9.
    Wennberg, Christian L.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Zocher, Florian
    Van der Spoel, David
    Pohl, Peter
    Hub, Jochen S.
    Unexpected Effects of Cholesterol on Membrane Permeability2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 2, p. 192A-193AArticle in journal (Other academic)
  • 10.
    Wennberg, Christian
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Murtola, Teemu
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Lattice Summation of Lennard-Jones Interactions in Bilayer Simulations has Critical Effects on Surface Tension2012In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, no 3, p. 172A-173AArticle in journal (Other academic)
  • 11.
    Wennberg, Christian
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Narangifard, Ali
    Lundborg, Magnus
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Norlén, Lars
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
    Structural transitions in ceramide cubic phases during formation of the human skin barrier2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086Article in journal (Other academic)
    Abstract [en]

    The stratum corneum is the outer-most layer of the human skin, and constitutes the primary barrier to penetration of external substances. The barrier function of the stratum corneum is primarily located to its extracellular space, which consists of long-chain ceramides, free fatty acids and cholesterol organised into a stacked lamellar bilayer structure. Recent experimental studies have shown that these lamellar structures are formed through a structural reorganization of glycosylceramide-based bilayers, folded in three dimensions with a cubic-like symmetry. Here we present coarse-grained molecular dynamics simulations of human ceramide- and glycosylceramide bilayer structures with gyroid cubic symmetry. The bilayer structures with glycosylceramides are able to maintain the cubic symmetry, while the bilayer structures with ceramides collapse into a stacked lamellar bilayer structure as the water content is reduced.

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