Richard Tjörnhammar

Phase transitions in coarse-grained lipid bilayers containing cholesterol by molecular dynamics simulations.

Coarse-grained simulations of model membranes containing mixtures of phospholipid and cholesterol molecules at different concentrations and temperatures have been performed. A random mixing without tendencies for segregation or formation of domains was observed on spatial scales corresponding to a few thousand lipids and timescales up to several microseconds. The gel-to-liquid crystalline phase transition is successively weakened with increasing amounts of cholesterol without disappearing completely even at a concentration of cholesterol as high as 60%. The phase transition temperature increases slightly depending on the cholesterol concentration. The gel phase system undergoes a transition with increasing amounts of cholesterol from a solid-ordered phase into a liquid-ordered one. In the solid phase, the amplitude of the oscillations in the radial distribution function decays algebraically with a prefactor that goes to zero at the solid-liquid transition.

Reparameterized United Atom Model for Molecular Dynamics Simulations of Gel and Fluid Phosphatidylcholine Bilayers

A new united atom parametrization of diacyl lipids like dipalmitoylphosphatidylcholine (DPPC) and the dimyristoylphosphatidylcholine (DMPC) has been constructed based on ab initio calculations to obtain fractional charges and the dihedral potential of the hydrocarbon chains, while the Lennard-Jones parameters of the acyl chains were fitted to reproduce the properties of liquid hydrocarbons. The results have been validated against published experimental X-ray and neutron scattering data for fluid and gel phase DPPC. The derived charges of the lipid phosphatidylcholine (PC) headgroup are shown to yield dipole components in the range suggested by experiments. The aim has been to construct a new force field that retains and improves the good agreement for the fluid phase and at the same time produces a gel phase at low temperatures, with properties coherent with experimental findings. The gel phase of diacyl-PC lipids forms a regular triangular lattice in the hydrocarbon region. The global bilayer tilt obtains an azimuthal value of 31° and is aligned between lattice vectors in the bilayer plane. We also show that the model yields a correct heat of melting as well as decent heat capacities in the fluid and gel phase of DPPC.

Molecular dynamics simulations of Zn2+ coordination in protein binding sites

A systematic molecular dynamics (MD) study of zinc binding to a peptide that mimics the structural binding site of horse liver alcohol dehydrogenase (HLADH) has been conducted. The four zinc binding cysteines were successively mutated into alanines to study the stability, zinc coordination, and free energy of binding. The zinc ion is coordinated to four sulfurs in the native peptide as in x-ray structures of HLADH. When the cysteines are replaced by alanines, the zinc coordinating sulfurs are replaced by waters and/or polypeptide backbone carbonyl oxygens. With two or fewer cysteines, the coordination number increases from four to six, while the coordination number varies between four and six with three cysteines depending on which of the cysteines that is replaced by an alanine. The binding free energies of zinc to the proteins were calculated from MD free energy integration runs to which corrections from quantum mechanical cluster calculations were added. There is a reasonable correlation with experimental binding free energies [T. Bergman et al., Cell. Mol. Life Sci. 65, 4019 (2008)]. For the chains with the lowest structural fluctuations and highest free energies lower coordination numbers for zinc are obtained. Finally, x-ray absorption fine structure spectra were calculated from the MD structures.

Laboratory x-ray micro imaging: Sources, optics, systems and applications

We summarize the recent progress in laboratory-scale soft and hard x-ray micro imaging in Stockholm. Our soft x-ray work is based on liquid-jet laser-plasma sources which are combined with diffractive and multilayer optics to form laboratory x-ray microscopes. In the hard x-ray regime the imaging is based on a liquid-metal-jet electron-impact source which provides the necessary coherence to allow phase-contrast imaging with high fidelity.

The shape and free energy of a lipid bilayer surrounding a membrane inclusion.

Membrane inclusion interactions are studied within the scope of continuum theory. We show that the free energy functional for the membrane thickness can be rewritten as a constant times a dimensionless integral. For cylindrical inclusions, the resulting differential equation gives a thickness profile that depends on the radius of the cylinder and one single lipid property, a correlation length that is determined by the ratio of the thickness compressibility and bending moduli. The solutions decay in a non-monotonic fashion with one single observable minimum. A solution for planar geometry may either be explicitly constructed or obtained by letting the radius of the cylinder go to infinity. In dimensionless units the initial derivative of the thickness profile is universal and equal to -1/√2. In physical units, the derivative depends on the size of the hydrophobic mismatch as well as the membrane correlation length and will usually be fairly small but clearly non-zero. The line tension between the protein inclusion and a fluid phase membrane will depend on the hydrophobic mismatch and be of the order of 10 pN (larger for the gel phase). This results in free energy costs for the inclusion that will be up to tens of kJ/mol (in the fluid phase).

The Shape and Free Energy of a Lipid Bilayer Surrounding a Membrane Inclusion

Membrane inclusion interactions are studied within the scope of continuum theory. We show that the free energy functional for the membrane thickness can be rewritten as a constant times a dimensionless integral. For cylindrical inclusions, the resulting differential equation gives a thickness profile that depends on the radius of the cylinder and one single lipid property, a correlation length that is determined by the ratio of the thickness compressibility and bending moduli. The solutions decay in a non-monotonic fashion with one single observable minimum. A solution for planar geometry may either be explicitly constructed or obtained by letting the radius of the cylinder go to infinity. In dimensionless units the initial derivative of the thickness profile is universal and equal to −1/√2. In physical units, the derivative depends on the size of the hydrophobic mismatch as well as the membrane correlation length and will usually be fairly small but clearly non-zero. The line tension between the protein inclusion and a fluid phase membrane will depend on the hydrophobic mismatch and be of the order of 10 pN (larger for the gel phase). This results in free energy costs for the inclusion that will be up to tens of kJ/mol (in the fluid phase)

Structural Correlations and Thermodynamics of the Gel Phase in Lipid Bilayers

We simulate biological membranes using the course grained MARTINI approach. Two dimensional distribution functions show that the gel phase is a well ordered hexagonal lattice. The transition from fluid to gel undergoes an intermediary phase with significant radial and angular correlations. Long range structural correlation along the lattice vectors show that the peak decay of this long lived pre-gel phase is exponential. We also show that the radial distributions of both gel and intermediary phase have sixfold anisotropy and that the angular correlations of the lattice in the gel phase quickly goes to a constant, concurrent with the results for a thermally perturbed hexagonal lattice. The pre-gel phase exhibit angular correlations that decay slowly to a constant. Furthermore we calculate the heat capacity and heat of formation of these two transitions via a slow simulated annealing scheme. We find sharp transitions between these phases and heats of formation close to differential scanning calorimetry data for the main- and pre-transition.