Calcium ions do not influence the Aß(25-35) triggered morphological changes of lipid membranes.

We have studied the effect of calcium ions (Ca2+) at various concentrations on the structure of lipid vesicles in the presence of amyloid-beta peptide Aß(25-35). In particular, we have investigated the influence of calcium ions on the formation of recently documented bicelle-like structures (BLSs) emerged as a result of Aß(25-35) triggered membrane disintegration. First, we have shown by using small-angle X-ray and neutron scattering that peptide molecules rigidify the lipid bilayer of gel phase DPPC unilamellar vesicles (ULVs), while addition of the calcium ions to the system hinders this effect of Aß(25-35). Secondly, the Aß(25-35) demonstrates a critical peptide concentration at which the BLSs reorganize from ULVs due to heating and cooling the samples through the lipid main phase transition temperature (Tm). However, addition of calcium ions does not affect noticeably the Aß-induced formation of BLSs and their structural parameters, though the changes in peptide's secondary structure, e.g. the increased α-helix fraction, has been registered by circular dichroism spectroscopy. Finally, according to 31P nuclear magnetic resonance (NMR) measurements, calcium ions do not affect the lipid-peptide arrangement in BLSs and their ability to align in the magnetic field of NMR spectrometer. The influences of various concentrations of calcium ions on the lipid-peptide interactions may prove biologically important because their local concentrations vary widely in in-vivo conditions. In the present work, calcium ions were investigated as a possible tool aimed at regulating the lipid-peptide interactions that demonstrated the disruptive effect of Aß(25-35) on lipid membranes.

Reflectometry and molecular dynamics study of the impact of cholesterol and melatonin on model lipid membranes.

The effect of melatonin and/or cholesterol on the structural properties of a model lipid bilayer prepared from 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) has been investigated both experimentally and via molecular dynamics (MD) simulations. Neutron reflectometry experiments performed with single supported membranes revealed changes in lipid bilayer thickness upon the introduction of additional components. While the presence of cholesterol led to an increase in membrane thickness, the opposite effect was observed in the case of melatonin. The results obtained are in a good agreement with MD simulations which provided further information on the organization of components within the systems examined, indicating a mechanism underlying the membranes' thickness changes due to cholesterol and melatonin that had been observed experimentally. Cholesterol and melatonin preferentially accumulate in different membrane regions, presumably affecting the conformation of lipid hydrophobic moieties differently, and in turn having distinct impacts on the structure of the entire membrane. Our findings may be relevant for understanding the effects of age-related changes in cholesterol and melatonin concentrations, including those in the brains of individuals with Alzheimer's disease.

Investigating the competitive effects of cholesterol and melatonin in model lipid membranes.

We have studied the impact of cholesterol and/or melatonin on the static and dynamical properties of bilayers made of DPPC or DOPC utilizing neutron scattering techniques, Raman spectroscopy and molecular dynamics simulations. While differing in the amplitude of the effect due to cholesterol or melatonin when comparing their interactions with the two lipids, their addition ensued recognizable changes to both types of bilayers. As expected, based on the two-component systems of lipid/cholesterol or lipid/melatonin studied previously, we show the impact of cholesterol and melatonin being opposite and competitive in the case of three-component systems of lipid/cholesterol/melatonin. The effect of cholesterol appears to prevail over that of melatonin in the case of structural properties of DPPC-based bilayers, which can be explained by its interactions targeting primarily the saturated lipid chains. The dynamics of hydrocarbon chains represented by the ratio of trans/gauche conformers reveals the competitive effect of cholesterol and melatonin being somewhat more balanced. The additive yet opposing effects of cholesterol and melatonin have been observed also in the case of structural properties of DOPC-based bilayers. We report that cholesterol induced an increase in bilayer thickness, while melatonin induced a decrease in bilayer thickness in the three-component systems of DOPC/cholesterol/melatonin. Commensurately, by evaluating the projected area of DOPC, we demonstrate a lipid area decrease with an increasing concentration of cholesterol, and a lipid area increase with an increasing concentration of melatonin. The demonstrated condensing effect of cholesterol and the fluidizing effect of melatonin appear in an additive manner upon their mutual presence.

Cation-Zwitterionic Lipid Interactions Are Affected by the Lateral Area per Lipid.

Interactions of the divalent cations Ca2+ and Mg2+ with the zwitterionic lipid bilayers prepared of a fully saturated dipalmitoylphosphatidylcholine (DPPC) or a di-monounsaturated dioleoylphosphatidylcholine (DOPC) were studied by using the neutron scattering methods and molecular dynamics simulations. The effect on the bilayer structural properties confirms the direct interactions in all cases studied. The changes are observed in the bilayer thickness and lateral area. The extent of these structural changes, moreover, suggests various mechanisms of the cation-lipid interactions. First, we have observed a small difference when studying DPPC bilayers in the gel and fluid phases, with somewhat larger effects in the former case. Second, the hydration proved to be a factor in the case of DOPC bilayers, with the larger effects in the case of less hydrated systems. Most importantly, however, there was a qualitative difference between the results of the fully hydrated DOPC bilayers and the others examined. These observations then prompt us to suggest an interaction model that is plausibly governed by the lateral area of lipid, though affected indirectly also by the hydration level. Namely, when the interlipid distance is small enough to allow for the multiple lipid-ion interactions, the lipid-ion-lipid bridges are formed. The bridges impose strong attractions that increase the order of lipid hydrocarbon chains, resulting in the bilayer thickening. In the other case, when the interlipid distance extends beyond a limiting length corresponding to the area per lipid of ∼65 Å2, Mg2+ and Ca2+ continue to interact with the lipid groups by forming the separate ion-lipid pairs. As the interactions proposed affect the lipid membrane structure in the lateral direction, they may prove to play their role in other mechanisms lying within the membrane multicomponent systems and regulating for example the lipid-peptide-ion interactions.

Effect of mutant NMDA receptors on the oscillations in a model of hippocampus.

A computation approach to identify the effect of missense mutations on the protein function is proposed. Using molecular dynamics simulation we have analyzed the gating kinetics of mutant NMDA synaptic receptors carrying mutations in their NR2 subunits. Analysis of channel geometry and Mg ion binding allowed to estimate the receptor conductivity. As a result, it was possible to identify the effect of these mutations on the generation of theta and gamma rhythms by the hippocampal neural network. Obtained results can be adapted for the analysis and evaluation of possible cognitive impairments caused by neurological diseases or consequences of radiation and other negative factors.

Calcium and Zinc Differentially Affect the Structure of Lipid Membranes.

Interactions of calcium (Ca2+) and zinc (Zn2+) cations with biomimetic membranes made of dipalmitoylphosphatidylcholine (DPPC) were studied by small angle neutron diffraction (SAND). Experiments show that the structure of these lipid bilayers is differentially affected by the two divalent cations. Initially, both Ca2+ and Zn2+ cause DPPC bilayers to thicken, while further increases in Ca2+ concentration result in the bilayer thinning, eventually reverting to having the same thickness as pure DPPC. The binding of Zn2+, on the other hand, causes the bilayers to swell to a maximum thickness, and the addition of more Zn2+ does not result in a further thickening of the membrane. Agreement between our results obtained using oriented planar membranes and those from vesicular samples implies that the effect of cations on bilayer thickness is the result of electrostatic interactions, rather than geometrical constraints due to bilayer curvature. This notion is further reinforced by MD simulations. Finally, the radial distribution functions reveal a strong interaction between Ca2+ and the phosphate oxygens, while Zn2+ shows a much weaker binding specificity.