Molecular dynamics simulation of Bombolitin II in the dipalmitoylphosphatidylcholine membrane bilayer

The orientation behavior of Bombolitin II (BLT2) in the dipalmitoylphosphatidylcholine membrane bilayer was investigated by using molecular-dynamics simulation. During the 20-ns simulation, the BLT2 began to tilt and finally reached the angle of 51° from the membrane-normal. The structure of the peptide formed the amphipathic α-helical structure during the entire simulation time. The peptide tilts with its hydrophobic side faced to the hydrophobic core of the bilayer. We analyzed the mechanism of the tilting behavior of the peptide associated with the membrane in detail. The analysis showed that the hydrogen-bond interaction and the electrostatic interaction were found to exist between Lys¹² and a lipid molecule. These interactions are considered to work as an important factor in tilting the peptide to the membrane-normal.     

Molecular dynamics simulation of a dipalmitoylphosphatidylcholine bilayer with NaCl

Molecular dynamics simulations are performed on two hydrated dipalmitoylphosphatidylcholine bilayer systems: one with pure water and one with added NaCl. Due to the rugged nature of the membrane/electrolyte interface, ion binding to the membrane surface is characterized by the loss of ion hydration. Using this structural characterization, binding of Na(+) and Cl(-) ions to the membrane is observed, although the binding of Cl(-) is seen to be slightly weaker than that of Na(+). Dehydration is seen to occur to a different extent for each type of ion. In addition, the excess binding of Na(+) gives rise to a net positive surface charge density just outside the bilayer. The positive density produces a positive electrostatic potential in this region, whereas the system without salt shows an electrostatic potential of zero.     

Molecular dynamics simulation of dipalmitoylphosphatidylcholine modified with a MTSL nitroxide spin label in a lipid membrane

We investigate the interaction between dipalmitoylphosphatidylcholine (DPPC) and a nitroxide spin label in order to understand its influences on lipid structure and dynamics using molecular dynamics simulations. The system was modified by covalently attaching nitroxide spin labels to the headgroups of two DPPC molecules. (S-(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl methanesulfonothioate) (MTSL) was used as the spin label. The label position and dynamics were analyzed as was the impact of the modified DPPC on the structure of the surrounding lipids. The modified DPPC molecules locate closer to the center of the membrane than unmodified DPPC molecules. The rotation of the spin label is unrestricted, but there are favored orientations. MTSL depresses the deuterium order parameters of the carbon atoms close to the headgroup in surrounding DPPC molecules. The spin label has no impact on order parameters of carbon atoms at the end of the lipid tails. The lateral diffusion constant of the modified DPPC is indistinguishable from unmodified DPPC molecules. These novel computational results suggest an experimental validation.     

Structure of dipalmitoylphosphatidylcholine/cholesterol bilayer at low and high cholesterol concentrations: molecular dynamics simulation.

By using molecular dynamics simulation technique we studied the changes occurring in membranes constructed of dipalmitoylphosphatidylcholine (DPPC) and cholesterol at 8:1 and 1:1 ratios. We tested two different initial arrangements of cholesterol molecules for a 1:1 ratio. The main difference between two initial structures is the average number of nearest-neighbor DPPC molecules around the cholesterol molecule. Our simulations were performed at constant temperature (T = 50 degrees C) and pressure (P = 0 atm). Durations of the runs were 2 ns. The structure of the DPPC/cholesterol membrane was characterized by calculating the order parameter profiles for the hydrocarbon chains, atom distributions, average number of gauche defects, and membrane dipole potentials. We found that adding cholesterol to membranes results in a condensing effect: the average area of membrane becomes smaller, hydrocarbon chains of DPPC have higher order, and the probability of gauche defects in DPPC tails is lower. Our results are in agreement with the data available from experiments.     

Molecular dynamics simulation of a phospholipid membrane

We present the results of molecular dynamics (MD) simulations of a phospholipid membrane in water, including full atomic detail. The goal of the simulations was twofold: first we wanted to set up a simulation system which is able to reproduce experimental results and can serve as a model membrane in future simulations. This goal being reached it is then further possible to gain insight in to those properties that are experimentally more difficult to access. The system studied is dipalmitoylphosphatidylcholine/water, consisting of 5408 atoms. Using original force field parameters the membrane turned out to approach a gel-like state. With slight changes of the parameters, the system adopted a liquid-crystalline state. Separate 80 ps runs were performed on both the gel and liquid-crystalline systems. Comparison of MD results with reliable experimental data (bilayer repeat distance, surface area per lipid, tail order parameters, atom distributions) showed that our simulations, especially the one in the liquid-crystalline phase, can serve as a realistic model for a phospholipid membrane. Further analysis of the trajectories revealed valuable information on various properties. In the liquid-crystalline phase, the interface turns out to be quite diffuse, with water molecules penetrating into the bilayer to the position of the carbonyl groups. The 10–90% width of the interface turns out to be 1.3 nm and the width of the hydrocarbon interior 3.0 nm. The headgroup dipoles are oriented at a small angle with respect to the bilayer plane. The resulting charge distribution is almost completely cancelled by the water molecules. The electron density distribution shows a large dip in the middle of the membrane. In this part the tails are more flexible. The mean life time between dihedral transitions is 20 ps. The average number of gauche angles per tail is 3.5. The occurrence of kinks is not a significant feature.Abbreviations MD molecular dynamics - DPPC dipalmitoylphosphatidylcholine - SPC simple point charges - DPPE dipalmitoylphosphatidylethanolamine Correspondence to: H. J. C. Berendsen     

Molecular dynamics simulation of a phosphatidylglycerol membrane

Although molecular dynamics simulations are an important tool for studying membrane systems, relatively few simulations have used anionic lipids. This paper reports the first simulation of a pure phosphatidylglycerol (PG) bilayer. The properties of this equilibrated palmitoyloleoylphosphatidylglycerol membrane agree with experimental observations of PG membranes and with previous simulations of monolayers and mixed bilayers containing PG lipids. These simulations also provide interesting insights into hydrogen bonding interactions in PG membranes. This equilibrated membrane will be a useful starting point for simulations of membrane proteins interacting with PG lipids.     

Molecular dynamics simulations of phospholipid bilayers with cholesterol

To investigate the microscopic interactions between cholesterol and lipids in biological membranes, we have performed a series of molecular dynamics simulations of large membranes with different levels of cholesterol content. The simulations extend to 10 ns, and were performed with hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers. The bilayers contain 1024 lipids of which 0-40% were cholesterol and the rest DPPC. The effects of cholesterol on the structure and mesoscopic dynamics of the bilayer were monitored as a function of cholesterol concentration. The main effects observed are a significant ordering of the DPPC chains (as monitored by NMR type order parameters), a reduced fraction of gauche bonds, a reduced surface area per lipid, less undulations--corresponding to an increased bending modulus for the membrane, smaller area fluctuations, and a reduced lateral diffusion of DPPC-lipids as well as cholesterols.     

Molecular dynamics simulation of melittin in a dimyristoylphosphatidylcholine bilayer membrane.

Molecular dynamics trajectories of melittin in an explicit dimyristoyl phosphatidylcholine (DMPC) bilayer are generated to study the details of lipid-protein interactions at the microscopic level. Melittin, a small amphipathic peptide found in bee venom, is known to have a pronounced effect on the lysis of membranes. The peptide is initially set parallel to the membrane-solution interfacial region in an alpha-helical conformation with unprotonated N-terminus. Solid-state nuclear magnetic resonance (NMR) and polarized attenuated total internal reflectance Fourier transform infrared (PATIR-FTIR) properties of melittin are calculated from the trajectory to characterize the orientation of the peptide relative to the bilayer. The residue Lys7 located in the hydrophobic moiety of the helix and residues Lys23, Arg24, Gln25, and Gln26 at the C-terminus hydrophilic form hydrogen bonds with water molecules and with the ester carbonyl groups of the lipids, suggesting their important contribution to the stability of the helix in the bilayer. Lipid acyl chains are closely packed around melittin, contributing to the stable association with the membrane. Calculated density profiles and order parameters of the lipid acyl chains averaged over the molecular dynamics trajectory indicate that melittin has effects on both layers of the membrane. The presence of melittin in the upper layer causes a local thinning of the bilayer that favors the penetration of water through the lower layer. The energetic factors involved in the association of melittin at the membrane surface are characterized using an implicit mean-field model in which the membrane and the surrounding solvent are represented as structureless continuum dielectric material. The results obtained by solving the Poisson-Bolztmann equation numerically are in qualitative agreement with the detailed dynamics. The influence of the protonation state of the N-terminus of melittin is examined. After 600 ps, the N-terminus of melittin is protonated and the trajectory is continued for 400 ps, which leads to an important penetration of water molecules into the bilayer. These observations provide insights into how melittin interacts with membranes and the mechanism by which it enhances their lysis.     

Molecular dynamics simulation of the structure of dimyristoylphosphatidylcholine bilayers with cholesterol, ergosterol, and lanosterol

Five molecular dynamics computer simulations were performed on different phospholipid:sterol membrane systems in order to study the influence of sterol structure on membrane properties. Three of these simulated bilayer systems were composed of a 1:8 sterol:phospholipid ratio, each of which employed one of the sterol molecules: cholesterol, ergosterol, and lanosterol. The two other simulations were of a bilayer with a 1:1 sterol:phospholipid ratio. These simulations employed cholesterol and lanosterol, respectively, as their sterol components. The observed differences in simulations with cholesterol and lanosterol may have their implication on the form of the phospholipid/sterol phase diagram.     

Molecular dynamics simulation of spontaneous membrane fusion during a cubic-hexagonal phase transition

We report a molecular dynamics simulation of the phase transition of monoolein from an inverted cubic phase to an inverted hexagonal phase. The transition proceeds via an intermediate structure consisting of water channels in a cubic geometry, in agreement with the predictions of the modified stalk theory (Siegel, 1999). Two mechanisms are identified by which the topology changes during the transition. Bilayer fusion proceeds via the formation of trans-monolayer contacts, whereas bilayer rupture is observed as a gradual thinning of each monolayer.     

Molecular dynamics simulation of the unfolding of individual bacteriorhodopsin helices in sodium dodecyl sulfate micelles

We report molecular dynamics simulations of the trends in the changes in secondary structure of the seven individual helices of bacteriorhodopsin when inserted into sodium dodecyl sulfate (SDS) micelles, and their dependence on the amino acid sequence. The results indicate that the partitioning of the helices in the micelles and their stability are dependent on the hydrophobicity of the transmembrane segments. Helices A, B, and E are stable and retain their initial secondary structure throughout the 100 ns simulation time. In contrast, helices C, D, F, and G show structural perturbations within the first 10 ns. The instabilities are localized near charged residues within the transmembrane segments. The overall structural instability of the helix is correlated with its partitioning to the surface of the micelle and its interaction with polar groups there. The in silico experiments were performed to complement the in vitro experiments that examined the partial denaturation of bacteriorhodopsin in SDS described in the preceding article (DOI 10.1021/bi201769z ). The simulations are consistent with the trends revealed by the experimental results but strongly underestimate the extent of helix to extended coil transformation. The reason may be either that the sampling time was not sufficiently long or, more interestingly, that interhelix residue interactions play a role in the unfolding of the helices.     

Molecular dynamics simulation of proton transport near the surface of a phospholipid membrane

The structural and dynamical properties of a hydrated proton near the surface of DMPC membrane were studied using a molecular dynamics simulation. The proton transport between water molecules was modeled using the second generation multistate empirical valence bond model. The proton diffusion was found to be inhibited at the membrane surface. The potential of mean force for the proton adsorption to the membrane surface and its release back into the bulk water was also determined, yielding a small barrier in each direction. An efficient algorithm for Ewald summation calculations for the multistate empirical valence bond model is also introduced.     

Molecular dynamics simulation of interaction between phospholipid membrane and pyrazine and its derivatives

We have performed a comparative molecular dynamics simulation of the diffusion process of the heterocyclic compound pyrazine and its methylated derivatives into the model membrane phospholipid bilayer. Several structural and dynamical bilayer parameters were measured, and qualitative interrelations between parameter changes and the substituted pyrazine structure were studied. The simulation results support the hypothesis that molecular mechanisms of biological effects of substituted pyrazines involve dissolution of the effector molecule in the membrane bilayer and subsequent changes in bilayer properties. This stage can provide the means for pyrazine molecules to interact with integral membrane proteins, directly or indirectly through the changed lipid environment of the protein.     

Molecular dynamics simulation of the tubulin dimer with cytostatics

Colchicin, podophylotoxin and indibulin are natural cytostatics that are used in the treatment of neoplasms. But applications of those compounds are rather restricted due to the high toxicity and low specificity. It seems very promising to investigate possibility to design new analogs of the above mentioned drugs that will possess higher cytostatic activity and less toxicity. For this purpose we see computer modeling experiments of tubulin and above mentioned compounds interaction as a powerful approach to design new artificial cytostatics with desired properties. In the current study the CHARMM software of protein-ligand interaction molecular dynamics method has been used. Particularly the following strategy has been applied. Molecules of the cytostatits have been positioned at several random positions around binding sites of tubulin and after energy minimization several binding sites have been identified on the tubulin macromolecule. In these binding sites structural changes that may be responsible for tubulin polymerization have been detected.     

Molecular dynamics simulations on the interaction of the transmembrane NavAb channel with cholesterol and lipids in the membrane

Increased cholesterol levels are associated with multiple pathological conditions. In this work, molecular dynamics simulations were applied to observe the influence of membrane cholesterol levels on a voltage-gated sodium channel. Different lipid compositions are modeled around the channel to obtain information about the possible effects by which cholesterol influences Na_vAb channels. Cholesterol was normally not directly interacting with either the closed or inactivated conformation. Cholesterol increased lipid packing implying that it plays a crucial role in restricting lipid movement in the region around 1 nm of the channel in a 1-palmitoyl-2-oeleoyl phosphatidylcholine matrix. Our results provide the first computational indication of an indirect modulation of Na_vAb channels by membrane cholesterol.     

Molecular dynamics simulation and steered molecular dynamics simulation on irisin dimers

Irisin is found closely associated with promoting the browning of beige fat cells in white adipose tissue. The crystal structure reveals that irisin forms a continuous inter-subunit β-sheet dimer. Here, molecular dynamics (MD) simulation and steered molecular dynamics (SMD) simulation were performed to investigate the dissociation process and the intricate interactions between the two irisin monomers. In the process of MD, the interactions between the monomers were roughly analyzed through the average numbers of both hydrophobic contacts and H-bonds. Then, SMD was performed to investigate the accurate interaction energy between the monomers. By the analysis of dissociation energy, the van der Waals (vdW) force was identified as the major energy to maintain the dimer structure, which also verified the results of MD simulation. Meanwhile, 11 essential residues were discovered by the magnitude of rupture force during dissociation. Among them, residues Arg75, Glu79, Ile77, Ala88, and Trp90 were reported in a previous study using the method of mutagenesis and size exclusion chromatography, and several new important residues (Arg72, Leu74, Phe76, Gln78, Val80, and Asp91) were also identified. Interestingly, the new important residues that we discovered and the important residues that were reported are located in the opposite side of the β-sheet of the dimer.     

Molecular dynamics simulation of silicate glasses

Summary Although the structure of glasses is not really accessible by experimental methods, molecular dynamics is a very useful alternative, as we have tried to demonstrate in this chapter. The simulations reproduce the broad macroscopic features found in these glasses, both structural and transport-related, providing a basis for the more detailed atomic scale features found in the simulated structures. An understanding of important aspects of alkali ion transport, such as the mixed alkali effect and anomalous behaviour in some alumino-silicates, can thus be approached from the atomistic pictures of the glasses produced by the simulations. Although there is room for improvements to the potential models available, it should be clear that the further application of computer simulation methods, such as molecular dynamics, promises to provide much needed advances in glass science and engineering.     

Molecular dynamics simulations of membrane proteins

Membrane proteins control the traffic across cell membranes and thereby play an essential role in cell function from transport of various solutes to immune response via molecular recognition. Because it is very difficult to determine the structures of membrane proteins experimentally, computational methods have been increasingly used to study their structure and function. Here we focus on two classes of membrane proteins—ion channels and transporters—which are responsible for the generation of action potentials in nerves, muscles, and other excitable cells. We describe how computational methods have been used to construct models for these proteins and to study the transport mechanism. The main computational tool is the molecular dynamics (MD) simulation, which can be used for everything from refinement of protein structures to free energy calculations of transport processes. We illustrate with specific examples from gramicidin and potassium channels and aspartate transporters how the function of these membrane proteins can be investigated using MD simulations.     

Molecular dynamics simulation of Kv channel voltage sensor helix in a lipid membrane with applied electric field

In this article, we present the results of the molecular dynamics simulations of amphiphilic helix peptides of 13 amino-acid residues, placed at the lipid-water interface of dipalmitoylphosphatidylcholine bilayers. The peptides are identical with, or are derivatives of, the N-terminal segment of the S4 helix of voltage-dependent K channel KvAP, containing four voltage-sensing arginine residues (R1-R4). Upon changing the direction of the externally applied electric field, the tilt angle of the wild-type peptide changes relative to the lipid-water interface, with the N-terminus heading up with an outward electric field. These movements were not observed using an octane membrane in place of the dipalmitoylphosphatidylcholine membrane, and were markedly suppressed by 1), substituting Phe located one residue before the first arginine (R1) with a hydrophilic residue (Ser, Thr); or 2), changing the periodicity rule of Rs from at-every-third to at-every-fourth position; or 3), replacing R1 with a lysine residue (K). These and other findings suggest that the voltage-dependent movement requires deep positioning of Rs when the resting (inward) electric field is present. Later, we performed simulations of the voltage sensor domain (S1-S4) of Kv1.2 channel. In simulations with a strong electric field (0.1 V/nm or above) and positional restraints on the S1 and S2 helices, S4 movement was observed consisting of displacement along the S4 helix axis and a screwlike axial rotation. Gating-charge-carrying Rs were observed to make serial interactions with E183 in S1 and E226 in S2, in the outer water crevice. A 30-ns-backward simulation started from the open-state model gave rise to a structure similar to the recent resting-state model, with S4 moving vertically ∼6.7 Å. The energy landscape around the movement of S4 appears very ragged due to salt bridges formed between gating-charge-carrying residues and negatively charged residues of S1, S2, and S3 helices. Overall, features of S3 and S4 movements are consistent with the recent helical-screw model. Both forward and backward simulations show the presence of at least two stable intermediate structures in which R2 and R3 form salt bridges with E183 or E226, respectively. These structures are the candidates for the states postulated in previous gating kinetic models, such as the Zagotta-Hoshi-Aldrich model, to account for more than one transition step per subunit for activation.     

Molecular packing in steroid-lecithin monolayers,part II: Mixed films of cholesterol with dipalmitoylphosphatidylcholine and tetradecanoic acid

Mixed film studies of the systems cholesterol/tetradecanoic acid and cholesterol/dipalmitoylphosphatidylcholine have been carried out over the entire compositional range at 21°C. When compared on an acyl chain basis the condensing effects were found to be essentially independent of which host-lipid was utilized. The phase change of the host lipid was shifted to higher pressures, then broadened and eliminated. Maximal condensation occurred at just above 42 mol% for the cholesterol/DPPC system. In both systems the two components were initially found to be miscible at all proportions.The results are interpreted in terms of the molecular packing of cholesterol with acyl boundary layers, one significantly, one weakly affected. Maximum condensation is a result of packing that provides maximum cholesterol/acyl chain contact. Consideration is given to both long term stability of such mixed monolayers and the behaviour of the corresponding bilayer states.