Browsing by Subject "LIPID-MEMBRANES"

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  • Melcr, Josef; Martinez-Seara, Hector; Nencini, Ricky; Kolafa, Jiri; Jungwirth, Pavel; Ollila, O. H. Samuli (2018)
    Binding affinities and stoichiometries of Na+ and Ca2+ ions to phospholipid bilayers are of paramount significance in the properties and functionality of cellular membranes. Current estimates of binding affinities and stoichiometries of cations are, however, inconsistent due to limitations in the available experimental and computational methods. In this work, we improve the description of the binding details of Na+ and Ca2+ ions to a 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayer by implicitly including electronic polarization as a mean field correction, known as the electronic continuum correction (ECC). This is applied by scaling the partial charges of a selected state-of-the-art POPC lipid model for molecular dynamics simulations. Our improved ECC-POPC model reproduces not only the experimentally measured structural parameters for the ion-free membrane, but also the response of lipid headgroup to a strongly bound cationic amphiphile, as well as the binding affinities of Na+ and Ca2+ ions. With our new model, we observe on the one side negligible binding of Na+ ions to POPC bilayer, while on the other side stronger interactions of Ca2+ primarily with phosphate oxygens, which is in agreement with the previous interpretations of the experimental spectroscopic data. The present model results in Ca2+ ions forming complexes with one to three POPC molecules with almost equal probabilities, suggesting more complex binding stoichiometries than those from simple models used to interpret the NMR data previously. The results of this work pave the way to quantitative molecular simulations with realistic electrostatic interactions of complex biochemical systems at cellular membranes.
  • Mahalka, Ajay K.; Code, Christian; Jahromi, Behnam Rezai; Kirkegaard, Thomas; Jaattela, Marja; Kinnunen, Paavo K. J. (2011)
  • Maury, Carl Peter J. (2018)
    A crucial stage in the origin of life was the emergence of the first molecular entity that was able to replicate, transmit information, and evolve on the early Earth. The amyloid world hypothesis posits that in the pre-RNA era, information processing was based on catalytic amyloids. The self-assembly of short peptides into beta-sheet amyloid conformers leads to extraordinary structural stability and novel multifunctionality that cannot be achieved by the corresponding nonaggregated peptides. The new functions include self-replication, catalytic activities, and information transfer. The environmentally sensitive template-assisted replication cycles generate a variety of amyloid polymorphs on which evolutive forces can act, and the fibrillar assemblies can serve as scaffolds for the amyloids themselves and for ribonucleotides proteins and lipids. The role of amyloid in the putative transition process from an amyloid world to an amyloid-RNA-protein world is not limited to scaffolding and protection: the interactions between amyloid, RNA, and protein are both complex and cooperative, and the amyloid assemblages can function as protometabolic entities catalyzing the formation of simple metabolite precursors. The emergence of a pristine amyloid-based in-put sensitive, chiroselective, and error correcting information-processing system, and the evolvement of mutualistic networks were, arguably, of essential importance in the dynamic processes that led to increased complexity, organization, compartmentalization, and, eventually, the origin of life.
  • Poojari, Chetan; Wilkosz, Natalia; Lira, Rafael B.; Dimova, Rumiana; Jurkiewicz, Piotr; Petka, Rafal; Kepczynski, Mariusz; Rog, Tomasz (2019)
    1,6-Diphenyl-1,3,5-hexatriene (DPH) is one of the most commonly used fluorescent probes to study dynamical and structural properties of lipid bilayers and cellular membranes via measuring steady-state or time-resolved fluorescence anisotropy. In this study, we present a limitation in the use of DPH to predict the order of lipid acyl chains when the lipid bilayer is doped with itraconazole (ITZ), an antifungal drug. Our steady-state fluorescence anisotropy measurements showed a significant decrease in fluorescence anisotropy of DPH embedded in the ITZ-containing membrane, suggesting a substantial increase in membrane fluidity, which indirectly indicates a decrease in the order of the hydrocarbon chains. This result or its interpretation is in disagreement with the fluorescence recovery after photobleaching measurements and molecular dynamics (MD) simulation data. The results of these experiments and calculations indicate an increase in the hydrocarbon chain order. The MD simulations of the bilayer containing both ITZ and DPH provide explanations for these observations. Apparently, in the presence of the drug, the DPH molecules are pushed deeper into the hydrophobic membrane core below the lipid double bonds, and the probe predominately adopts the orientation of the ITZ molecules that is parallel to the membrane surface, instead of orienting parallel to the lipid acyl chains. For this reason, DPH anisotropy provides information related to the less ordered central region of the membrane rather than reporting the properties of the upper segments of the lipid acyl chains.
  • Kulig, Waldemar; Mikkolainen, Heikki; Olzynska, Agnieszka; Jurkiewicz, Piotr; Cwiklik, Lukasz; Hof, Martin; Vattulainen, Ilpo; Jungwirth, Pavel; Rog, Tomasz (2018)
    Translocation of sterols between cellular membrane leaflets is of key importance in membrane organization, dynamics, and signaling. We present a novel translocation mechanism that differs in a unique manner from the established ones. The bobbing mechanism identified here is demonstrated for tail-oxidized sterols, but is expected to be viable for any molecule containing two polar centers at the opposite sides of the molecule. The mechanism renders translocation across a lipid membrane possible without a change in molecular orientation. For tail-oxidized sterols, the bobbing mechanism provides an exceptionally facile means to translocate these signaling molecules across membrane structures and may thus represent an important pathway in the course of their biological action.
  • Catte, Andrea; Girych, Mykhailo; Javanainen, Matti; Loison, Claire; Melcr, Josef; Miettinen, Markus S.; Monticelli, Luca; Maatta, Jukka; Oganesyan, Vasily S.; Ollila, O. H. Samuli; Tynkkynen, Joona; Vilov, Sergey (2016)
    Despite the vast amount of experimental and theoretical studies on the binding affinity of cations -especially the biologically relevant Na+ and Ca2+ - for phospholipid bilayers, there is no consensus in the literature. Here we show that by interpreting changes in the choline headgroup order parameters according to the 'molecular electrometer' concept [Seelig et al., Biochemistry, 1987, 26, 7535], one can directly compare the ion binding affinities between simulations and experiments. Our findings strongly support the view that in contrast to Ca2+ and other multivalent ions, Na+ and other monovalent ions (except Li+) do not specifically bind to phosphatidylcholine lipid bilayers at sub-molar concentrations. However, the Na+ binding affinity was overestimated by several molecular dynamics simulation models, resulting in artificially positively charged bilayers and exaggerated structural effects in the lipid headgroups. While qualitatively correct headgroup order parameter response was observed with Ca2+ binding in all the tested models, no model had sufficient quantitative accuracy to interpret the Ca2+: lipid stoichiometry or the induced atomistic resolution structural changes. All scientific contributions to this open collaboration work were made publicly, using nmrlipids. blogspot.fi as the main communication platform.
  • Juhola, Hanna; Postila, Pekka A.; Rissanen, Sami; Lolicato, Fabio; Vattulainen, Ilpo; Rog, Tomasz (2018)
    Lipophilic neurotransmitters (NTs) such as dopamine are chemical messengers enabling neurotransmission by adhering onto the extracellular surface of the post-synaptic membrane in a synapse, followed by binding to their receptors. Previous studies have shown that the strength of the NT-membrane association is dependent on the lipid composition of the membrane. Negatively charged lipids such as phosphatidylserine, phosphatidylglycerol, and phosphatidic acid have been indicated to promote NT-membrane binding, however these anionic lipids reside almost exclusively in the intracellular leaflet of the post-synaptic membrane instead of the extracellular leaflet facing the synaptic cleft. Meanwhile, the extracellular leaflet is relatively rich in biologically relevant anionic gangliosides such as monosialotetrahexosylganglioside (GM1), yet the role of gangliosides in NT-membrane association is not clear. Here, we explored the role of GM1 in modulating the binding of dopamine and histamine (as amphipathicicationic NTs) as well as acetylcholine (as a hydrophilic/cationic NT) with the post-synaptic membrane surface. Atomistic molecular dynamics simulations and free energy calculations indicated that GM1 fosters membrane association of histamine and dopamine. For acetylcholine, this effect was not observed. The in silico results suggest that gangliosides form a charge-based vestibule in front of the post-synaptic membrane, attracting amphipathic NTs to the vicinity of the membrane. The results also stress the importance to understand the significance of the structural details of NTs, as exemplified by the GM1-acetylcholine interaction. In a larger context, the NT-membrane adherence, coupled to lateral diffusion in the membrane plane, is proposed to improve neurotransmission efficiency by advancing NT entry into the membrane-embedded ligand-binding sites. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Javanainen, Matti; Ollila, O. H. Samuli; Martinez-Seara, Hector (2020)
    Membrane proteins travel along cellular membranes and reorient themselves to form functional oligomers and proteinlipid complexes. Following the Saffman-Delbruck model, protein-radius sets the rate of this diffusive motion. However, it is unclear how this model, derived for ideal and dilute membranes, performs under crowded conditions of cellular membranes. Here, we study the rotational motion of membrane proteins using molecular dynamics simulations of coarse-grained membranes and 2-dimensional Lennard-Jones fluids with varying levels of crowding. We find that the Saffman-Delbruck model captures the size-dependency of rotational diffusion under dilute conditions where protein-protein interactions are negligible, whereas stronger scaling laws arise under crowding. Together with our recent work on lateral diffusion, our results reshape the description of protein dynamics in native membrane environments: The translational and rotational motions of proteins with small transmembrane domains are rapid, whereas larger proteins or protein complexes display substantially slower dynamics.
  • Laulumaa, Saara; Nieminen, Tuomo; Raasakka, Arne; Krokengen, Oda C.; Safaryan, Anushik; Hallin, Erik I.; Brysbaert, Guillaume; Lensink, Marc F.; Ruskamo, Salla; Vattulainen, Ilpo; Kursula, Petri (2018)
    Background: Myelin is a multilayered proteolipid sheath wrapped around selected axons in the nervous system. Its constituent proteins play major roles in forming of the highly regular membrane structure. P2 is a myelin-specific protein of the fatty acid binding protein (FABP) superfamily, which is able to stack lipid bilayers together, and it is a target for mutations in the human inherited neuropathy Charcot-Marie-Tooth disease. A conserved residue that has been proposed to participate in membrane and fatty acid binding and conformational changes in FABPs is Phe57. This residue is thought to be a gatekeeper for the opening of the portal region upon ligand entry and egress. Results: We performed a structural characterization of the F57A mutant of human P2. The mutant protein was crystallized in three crystal forms, all of which showed changes in the portal region and helix a2. In addition, the behaviour of the mutant protein upon lipid bilayer binding suggested more unfolding than previously observed for wild-type P2. On the other hand, membrane binding rendered F57A heat-stable, similarly to wild-type P2. Atomistic molecular dynamics simulations showed opening of the side of the discontinuous beta barrel, giving important indications on the mechanism of portal region opening and ligand entry into FABPs. The results suggest a central role for Phe57 in regulating the opening of the portal region in human P2 and other FABPs, and the F57A mutation disturbs dynamic cross-correlation networks in the portal region of P2. Conclusions: Overall, the F57A variant presents similar properties to the P2 patient mutations recently linked to Charcot-Marie-Tooth disease. Our results identify Phe57 as a residue regulating conformational changes that may accompany membrane surface binding and ligand exchange in P2 and other FABPs.