Biomedical subjects
Publications and source records attributed to Tomasz Róg.
Using extensive atomistic simulations, we show that there is a single experimentally accessible parameter--the sterol tilt--that can be used to determine a sterol's capability to induce order, and thus to promote, e.g., formation of lipid rafts. The observations also facilitate designing new effective sterols.
Anionic palmitoyloleoylphosphatidylglycerol (POPG) is one of the most abundant lipids in nature, yet its atomic-scale properties have not received significant attention. Here we report extensive 150-ns molecular dynamics simulations of a pure POPG lipid membrane with sodium counterions. It turns out that the average area per lipid of the POPG bilayer under physiological conditions is approximately 19% smaller than that of a bilayer built from its zwitterionic phosphatidylcholine analog, palmitoyloleoylphosphatidylcholine. This suggests that there are strong attractive interactions between anionic POPG lipids, which overcome the electrostatic repulsion between negative charges of PG headgroups. We demonstrate that interlipid counterion bridges and strong intra- and intermolecular hydrogen bonding play a key role in this seemingly counterintuitive behavior. In particular, the substantial strength and stability of ion-mediated binding between anionic lipid headgroups leads to complexation of PG molecules and ions and formation of large PG-ion clusters that act in a concerted manner. The ion-mediated binding seems to provide a possible molecular-level explanation for the low permeability of PG-containing bacterial membranes to organic solvents: highly polar interactions at the water/membrane interface are able to create a high free energy barrier for hydrophobic molecules such as benzene.
Stearoylsphingomyelin (SSM) bilayers containing 0, 22, and 50 mol % cholesterol (Chol) and a pentadecanoyl-stearoylphosphatidylcholine (15SPC) bilayer containing 22 mol % Chol were molecular dynamics simulated at two temperatures (37 degrees C and 60 degrees C). 15SPC is the best PC equivalent of SSM. The Chol effect on the SSM bilayer differs significantly from that on the 15SPC bilayer. At the same temperature and Chol content, H-bonding of Chol with SSM is more extensive than with 15SPC. SSM-Chol H-bonding anchors the OH group of Chol in the lower regions of the SSM-Chol bilayer interface. Such a location strengthens the influence of Chol on the SSM chains. In effect, the phase of the SSM-Chol bilayer containing 22 mol % Chol at 37 degrees C is shifted from the gel to the liquid-ordered phase, and the bilayer displays similar properties below and above the main phase-transition temperature for a pure SSM bilayer of approximately 45 degrees C. In contrast, due to a higher location, Chol is not able to change the phase of the 15SPC-Chol bilayer, which at 37 degrees C remains in the gel phase. Chol affects both the core and interface of the SSM bilayer. With increasing Chol content, the order of SSM chains and hydration of SSM headgroups increase, whereas polar interactions between lipids decrease.
A series of multi-nanosecond molecular dynamics (MD) simulations of wild-type cytochrome c and its spin-labeled variants with the methanethiosulfonate moiety attached at position C102 were performed (1) to elucidate the effect of the spin probe presence on the protein structure and (2) to describe the structure and dynamics of the spin-label moiety. Comparisons with the reference crystal structure of cytochrome c (PDB entry: 1YCC) indicate that the protein secondary structure is well preserved during simulations of the wild-type cytochrome c but slightly changed in simulations of the cytochrome c labeled at position C102. At the time scale covered in our simulations, the spin label exhibits highly dynamical behavior. The number of observed distinct conformations of the spin label moiety is between 3 and 13. The spin probe was found to form short-lived hydrogen bonds with the protein. Temporary hydrophobic interactions between the probe and the protein were also detected. The MD simulations directly show that the disulfide bond in the tether linking a spin probe with a protein strongly influence the behavior of the nitroxide group. The conformational flexibility and interaction with the protein are different for each of the two low energy conformations of the disulfide bond.
Desmosterol is an immediate precursor of cholesterol in the Bloch pathway of sterol synthesis and an abundant membrane lipid in specific cell types. The significance of the difference between the two sterols, an additional double bond at position C24 in the tail of desmosterol, is not known. Here, we provide evidence that the biophysical and functional characteristics of the two sterols differ and that this is because the double bond at C24 significantly weakens the sterol ordering potential. In model membranes, desmosterol was significantly weaker than cholesterol in promoting the formation or stability of ordered domains, and in mammalian cell membranes, desmosterol associated less avidly than cholesterol with detergent-resistant membranes. Atomic scale molecular dynamics simulations showed that the double bond gives rise to additional stress in the tail, creating a rigid structure between C24 and C27 and favoring tilting of desmosterol distinct from cholesterol. Functional effects of desmosterol in cell membranes were assessed upon acutely exchanging approximately 70% of cholesterol to desmosterol. This led to impaired raft-dependent signaling via the insulin receptor, whereas non-raft-dependent protein secretion was not affected. We suggest that the choice of cholesterol synthesis route may provide a physiological mechanism to modulate raft-dependent functions in cells.
We report the initial findings of 100 ns molecular dynamics simulations of the role of cellular membranes in general anaesthesia. The effect of xenon on hydrated dipalmitoylphosphatidylcholine bilayers is described. The xenon atoms were found to prefer the interfacial and central regions of the bilayer. The presence of xenon was observed to lead to a small increase in the surface area, membrane thickness, and order of the acyl chains.
Phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) are the main lipid components of the inner bacterial membrane. A computer model for such a membrane was built of palmitoyloleoyl PE (POPE) and palmitoyloleoyl PG (POPG) in the proportion 3:1, and sodium ions (Na+) to neutralize the net negative charge on each POPG (POPE-POPG bilayer). The bilayer was simulated for 25 ns. A final 10-ns trajectory fragment was used for analyses. In the bilayer interfacial region, POPEs and POPGs interact readily with one another via intermolecular hydrogen (H) bonds and water bridges. POPE is the main H-bond donor in either PEPE or PEPG H-bonds; PGPG H-bonds are rarely formed. Almost all POPEs are H-bonded and/or water bridged to either POPE or POPG but PE-PG links are favored. In effect, the atom packing in the near-the-interface regions of the bilayer core is tight. Na+ does not bind readily to lipids, and interlipid links via Na+ are not numerous. Although POPG and POPE comprise one bilayer, their bilayer properties differ. The average surface area per POPG is larger and the average vertical location of the POPG phosphate group is lower than those of POPE. Also, the alkyl chains of POPG are more ordered and less densely packed than the POPE chains. The main conclusion of this study is that in the PE-PG bilayer PE interacts more strongly with PG than with PE. This is a likely molecular-level event behind a regulating mechanism developed by the bacteria to control its membrane permeability and stability consisting in changes of the relative PG/PE concentration in the membrane.
A 15-ns molecular dynamics simulation of the fully hydrated dimyristoylphosphatidylcholine-cholesterol (DMPC-Chol) bilayer containing approximately 22 mol% Chol was carried out. An 8-ns trajectory was analysed to investigate the effect of Chol on the chain packing in the bilayer core. While the packing of DMPC chains on the smooth alpha-face side of the Chol ring is similar to that in the pure DMPC bilayer, the packing on the rough beta-face side is less regular and less tight. Two methyl groups located on the Chol beta-face disturb the packing; in effect, van der Waals (vdW) interactions between Chol rings and DMPC chains are weaker than the ones between sole DMPC chains. VdW interactions between an alkyl chain of DMPC and an isooctyl tail of Chol are similarly strong as those between two DMPC chains.
Molecular dynamics simulations of two monounsaturated phosphatidylcholine (PC) bilayers made of 1-palmitoyl-2-oleoyl-PC (POPC; cis-unsaturated) and 1-palmitoyl-2-elaidoyl-PC (PEPC; trans-unsaturated) were carried out to investigate the effect of a double bond in the PC beta-chain and its conformation on the bilayer core. Four nanosecond trajectories were used for analyses. A fully saturated 1,2-dimyristoyl-PC (DMPC) bilayer was used as a reference system. In agreement with experimental data, this study shows that properties of the PEPC bilayer are more similar to those of the DMPC than to the POPC bilayer. The differences between POPC and PEPC bilayers may be attributed to the different ranges of angles covered by the torsion angles beta10 and beta12 of the single bonds next to the double bond in the oleoyl (O) and elaidoyl (E) chains. Broader distributions of beta10 and beta12 in the E chain than in the O chain make the E chain more flexible. In effect, the packing of chains in the PEPC bilayer is similar to that in the DMPC bilayer, whereas that in the POPC bilayer is looser than that in the DMPC bilayer. The effect of the cis-double bond on torsions at the beginning of the O chain (beta4 and beta5) is similar to that of cholesterol on these torsions in a myristoyl chain.
Epicholesterol (Echol) is an epimeric form of cholesterol (Chol). A molecular dynamics simulation of the fully hydrated dimyristoylphosphatidylcholine-Echol (DMPC-Echol) bilayer membrane containing approximately 22 mol % of Echol was carried out for 5 ns. A 3-ns trajectory generated between 2 and 5 ns of molecular dynamics simulation was used for analyses to determine the effects of Echol on the membrane properties. As reference systems, pure DMPC and mixed DMPC-Chol bilayers were used. The study shows that Echol, like Chol, changes the organization of the bilayer/water interface and increases membrane order and condensation, but to a lesser degree. Effects of both sterols are based on the same atomic level mechanisms; their different strength arises from different vertical localizations of Echol and Chol hydroxyl groups in the membrane/water interface.
Molecular dynamics (MD) simulations complement experimental methods in studies of the structure and dynamics of lipid bilayers. The choice of algorithms employed in this computational method represents a trade-off between the accuracy and real calculation time. The largest portion of the simulation time is devoted to calculation of long-range electrostatic interactions. To speed-up evaluation of these interactions, various approximations have been used. The most common ones are the truncation of long-range interactions with the use of cut-offs, and the particle-mesh Ewald (PME) method. In this study, several multi-nanosecond cut-off and PME simulations were performed to establish the influence of the simulation protocol on the bilayer properties. Two bilayers were used. One consisted of neutral phosphatidylcholine molecules. The other was a mixed lipid bilayer consisting of neutral phosphatidylethanolamine and negatively charged phosphatidylglycerol molecules. The study shows that the cut-off simulation of a bilayer containing charge molecules generates artefacts; in particular the mobility and order of the charged molecules are vastly different from those determined experimentally. In the PME simulation, the bilayer properties are in general agreement with experimental data. The cut-off simulation of bilayers containing only uncharged molecules does not generate artefacts, nevertheless, the PME simulation gives generally better agreement with experimental data.