Lipopolysaccharide (LPS), a component of Gram-negative bacterial outer membranes, comprises three regions: lipid A, core oligosaccharide, and O-antigen polysaccharide. Using the CHARMM36 lipid and ...carbohydrate force fields, we have constructed a model of an Escherichia coli R1 (core) O6 (antigen) LPS molecule. Several all-atom bilayers are built and simulated with lipid A only (LIPA) and varying lengths of 0 (LPS0), 5 (LPS5), and 10 (LPS10) O6 antigen repeating units; a single unit of O6 antigen contains five sugar residues. From 1H,1H-NOESY experiments, cross-relaxation rates are obtained from an O-antigen polysaccharide sample. Although some experimental deviations are due to spin-diffusion, the remaining effective proton-proton distances show generally very good agreement between NMR experiments and molecular dynamics simulations. The simulation results show that increasing the LPS molecular length has an impact on LPS structure and dynamics and also on LPS bilayer properties. Terminal residues in a LPS bilayer are more flexible and extended along the membrane normal. As the core and O-antigen are added, per-lipid area increases and lipid bilayer order decreases. In addition, results from mixed LPS0/5 and LPS0/10 bilayer simulations show that the LPS O-antigen conformations at a higher concentration of LPS5 and LPS10 are more orthogonal to the membrane and less flexible. The O-antigen concentration of mixed LPS bilayers does not have a significant effect on per-lipid area and hydrophobic thickness. Analysis of ion and water penetration shows that water molecules can penetrate inside the inner core region, and hydration is critical to maintain the integrity of the bilayer structure.
Molecular simulations of biological molecules require an accurate description of molecular interactions through a force field (FF). The focus of this Perspective is on all-atom lipid FFs. Recent ...additions to the CHARMM36 lipid FF continue to expand a researcher’s ability to probe membrane structure and function with a wide variety of biologically important lipids. Currently, there is an effort to reduce the assumptions in all-atom lipid FFs. The inclusion of long-range dispersion interaction through particle-mesh Ewald is allowing for more accurate descriptions of lipid bilayer and monolayer properties without additional computational cost. Soon, simulations with lipid FFs will no longer depend on short-range cutoffs and will accurately represent long-range dispersion. This requires efficient FF parametrization with an automated approach due to FF complexity. In addition, polarizable FFs for lipids will be important for the next generation of simulations that accurately represent how molecule interactions respond to a varied environment.
Lipid bilayers play an important role in biological systems as they protect cells against unwanted chemicals and provide a barrier for material inside a cell from leaking out. In this paper, nearly ...30 μs of molecular dynamics (MD) simulations were performed to investigate phase transitions of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-phosphocholine (DPPC) lipid bilayers from the liquid crystalline (Lα) to the ripple (Pβ) and to the gel phase (Lβ). Our MD simulations accurately predict the main transition temperature for the single-component bilayers. A key focus of this work is to quantify the structure of the Pβ phase for DMPC and compare with measures from x-ray experiments. The Pβ major arm has similar structure to that of the Lβ, while the thinner minor arm has interdigitated chains and the transition region between these two regions has large chain splay and disorder. At lower temperatures, our MD simulations predict the formation of the Lβ phase with tilted fatty acid chains. The Pβ and Lβ phases are studied for mixtures of DMPC and DPPC and compare favorably with experiment. Overall, our MD simulations provide evidence for the relevancy of the CHARMM36 lipid force field for structures and add to our understanding of the less-defined Pβ phase.
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•CHARMM36 force field is accurate for the condensed lipid phases and the temperature range for pure and mixed lipid bilayers.•Simulations for large DMPC bilayer indicated potential match to the ripple wave length•Ripple minor arm consists of interdigitated chains and lipid chain splay (disorder) independent of system size•Tilt angle of acyl chains of DMPC bilayer in the gel phase was in great agreement with experimental result.
Modeling lipid bilayers using molecular simulations has progressed from short simulations of single-component lipids to currently having the ability to model complex cellular membranes with nearly ...100 different lipid types on a
s time scale. This perspective article presents a review of how the chemical physics field has provided insight into the structure and dynamics of accurate cellular membrane models. A short review of lipid force fields is presented, and how lower-resolution models can allow for assemblies and time scales not attainable with all-atom models. Key examples on membranes that mimic the lipid diversity seen in nature are provided for all-atom and coarse-grained lipid force fields. The article concludes with an outlook for the field on where there exist certain challenges (lipid diversity and leaflet concentration asymmetry) over the next several years. This is an exciting time to be a researcher in the field of modeling cellular membranes with ultimate goals to model not just an accurate cell membrane but in the future modeling a whole cell.
The C36 CHARMM lipid force field has been extended to include sphingolipids, via a combination of high-level quantum mechanical calculations on small molecule fragments, and validation by extensive ...molecular dynamics simulations on N-palmitoyl and N-stearoyl sphingomyelin. NMR data on these two molecules from several studies in bilayers and micelles played a strong role in the development and testing of the force field parameters. Most previous force fields for sphingomyelins were developed before the availability of the detailed NMR data and relied on x-ray diffraction of bilayers alone for the validation; these are shown to be too dense in the bilayer plane based on published chain order parameter data from simulations and experiments. The present simulations reveal O-H:::O-P intralipid hydrogen bonding occurs 99% of the time, and interlipid N-H:::O=C (26-29%, depending on the lipid) and N-H:::O-H (17–19%). The interlipid hydrogen bonds are long lived, showing decay times of 50 ns, and forming strings of lipids, and leading to reorientational correlation time of nearly 100 ns. The spontaneous radius of curvature for pure N-palmitoyl sphingomyelin bilayers is estimated to be 43–100 Å, depending on the assumptions made in assigning a bending constant; this unusual positive curvature for a two-tailed neutral lipid is likely associated with hydrogen bond networks involving the NH of the sphingosine group.
The CHARMM-GUI Membrane Builder (http://www.charmm-gui.org/input/membrane), an intuitive, straightforward, web-based graphical user interface, was expanded to automate the building process of ...heterogeneous lipid bilayers, with or without a protein and with support for up to 32 different lipid types. The efficacy of these new features was tested by building and simulating lipid bilayers that resemble yeast membranes, composed of cholesterol, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, palmitoyloleoylphosphatidylethanolamine, palmitoyloleoylphosphatidylamine, and palmitoyloleoylphosphatidylserine. Four membranes with varying concentrations of cholesterol and phospholipids were simulated, for a total of 170 ns at 303.15 K. Unsaturated phospholipid chain concentration had the largest influence on membrane properties, such as average lipid surface area, density profiles, deuterium order parameters, and cholesterol tilt angle. Simulations with a high concentration of unsaturated chains (73%, membraneunsat) resulted in a significant increase in lipid surface area and a decrease in deuterium order parameters, compared with membranes with a high concentration of saturated chains (60–63%, membranesat). The average tilt angle of cholesterol with respect to bilayer normal was largest, and the distribution was significantly broader for membraneunsat. Moreover, short-lived cholesterol orientations parallel to the membrane surface existed only for membraneunsat. The membranesat simulations were in a liquid-ordered state, and agree with similar experimental cholesterol-containing membranes.
The all-atom CHARMM36 (C36) force field is used to simulate bilayers of pure palmitoylsphingomyelin (PSM) as well as binary mixtures of PSM and stearoylsphingomyelin (SSM) at various cholesterol ...concentrations (X C) and temperatures. C36 simulation data is in good agreement with experimental deuterium order parameters and previous computational results, providing evidence of the utility of the force field for potentially studying more complex membranes. The area compressibility modulus is shown to achieve a large value of 2.82 ± 0.08 N/m in cholesterol-rich membranes (X C = 0.50). Surface area per lipid (SA/lip), tilt angle, membrane thicknesses, and acyl chain ordering are shown to have strong dependencies on cholesterol concentration. Relaxation times also indicate cholesterol dependence and show a strong preference for rotational axial motion over wobbling motion. Radial distribution functions and lipid clustering indicate strong relationships between lateral ordering and hydrogen bonding, which is long lived in SM membranes. These interactions lead to strong self-association of cholesterol at high concentrations, causing shielding from further SM–cholesterol interactions. The importance of a ternary component on SM–SM hydrogen bonds is revealed in light of previous results and is consequential in the modeling of lipid rafts.
All-atom models of the long periodicity phase (LPP) in the stratum corneum (SC) are studied using bilayer–slab–bilayer (sandwich) structures and multi-microsecond simulations. Linoleate promotes ...melting of the interior slab, which contains ceramide (Cer) in the posturing chain conformation, a structurally distinct conformation from full chain extension. The mechanism of Cer transitioning into full extension is characterized by initial anchoring of the head-proximal carbons and occurs over tens of nanoseconds. Free fatty acids translocate through the interior over hundreds of nanoseconds, while Cer and cholesterol take around a microsecond or longer to translocate. Electron density and neutron scattering length density profiles from simulation agree with experiment, and the high disorder of linoleate in CerEOS supports experiments with infrared spectroscopy and nuclear magnetic resonance. Lateral organization demonstrates dependence on lipid composition and bilayer thickness. To further validate the LPP model, umbrella sampling was used to calculate ethanol permeability in comparison with experiment (log(P) values obtained from modeling the SC’s multiple LPP layers are −7.6 and −6.6 cm/s, and that from experiment on cadaver skin is −6.65 cm/s). A “leapfrog” mechanism for ethanol permeation is proposed which is associated with its role as a topical enhancer. These models, the first experimentally verified atomistic sandwich models of the LPP, will aid in the design and optimization of transdermal drug delivery.
The inclusion of accurate yet computationally inexpensive lipid force fields (FF) is pertinent for the study of lipids and lipid-containing systems using molecular dynamics (MD). Within the past ...decade, the implementation and further expansion of a united atom (UA) FF for lipids have been developed in the CHARMM family of FFs. The most recent version of the UA presented more accurate descriptions of lipid properties for several phospholipids with saturated and monounsaturated chains, termed C36UAr. However, the original C36UAr model lacks parameters for an important class of lipids, such as sphingolipids. The focus of this article is to broaden the scope of the C36UAr chain model to incorporate these lipids. In this study, two common sphingolipids, N-palmitoyl sphingomyelin and N-stearoyl sphingomyelin are converted to a UA-chain representation and simulated to investigate the accuracy and speed over the all-atom FF model for sphingolipids. Improvements were found among multiple parameters, for example, in the surface area per lipid (SA/lip) and hydrogen order parameters, over the all-atom simulations of these sphingomyelins in C36, while as much as halving the simulation time for simulations of the same setup otherwise. Thus, the accuracy and efficiency found in this study are consistent with those found in the C36UAr model for phospholipids and expand the application of C36UAr to a wider array of membrane models to better match that in vivo.
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