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1.  Lipid Simulations: A Perspective on Lipids in Action 
In this article, we provide an overview of lipid simulations, describing how a computer can be used as a laboratory for lipid research. We briefly discuss the methodology of lipid simulations followed by a number of topical applications that show the benefit of computer modeling for complementing experiments. In particular, we show examples of cases in which simulations have made predictions of novel phenomena that have later been confirmed by experimental studies. Overall, the applications discussed in this article focus on the most recent state of the art and aim to provide a perspective of where the field of lipid simulations stands at the moment.
Atomistic and coarse-grained molecular dynamics simulations can accurately predict how lipid molecules behave in membranes, interact with proteins, and are trafficked within cells.
PMCID: PMC3062216  PMID: 21441592
2.  Lipid Exchange Mechanism of the Cholesteryl Ester Transfer Protein Clarified by Atomistic and Coarse-grained Simulations 
PLoS Computational Biology  2012;8(1):e1002299.
Cholesteryl ester transfer protein (CETP) transports cholesteryl esters, triglycerides, and phospholipids between different lipoprotein fractions in blood plasma. The inhibition of CETP has been shown to be a sound strategy to prevent and treat the development of coronary heart disease. We employed molecular dynamics simulations to unravel the mechanisms associated with the CETP-mediated lipid exchange. To this end we used both atomistic and coarse-grained models whose results were consistent with each other. We found CETP to bind to the surface of high density lipoprotein (HDL) -like lipid droplets through its charged and tryptophan residues. Upon binding, CETP rapidly (in about 10 ns) induced the formation of a small hydrophobic patch to the phospholipid surface of the droplet, opening a route from the core of the lipid droplet to the binding pocket of CETP. This was followed by a conformational change of helix X of CETP to an open state, in which we found the accessibility of cholesteryl esters to the C-terminal tunnel opening of CETP to increase. Furthermore, in the absence of helix X, cholesteryl esters rapidly diffused into CETP through the C-terminal opening. The results provide compelling evidence that helix X acts as a lid which conducts lipid exchange by alternating the open and closed states. The findings have potential for the design of novel molecular agents to inhibit the activity of CETP.
Author Summary
Coronary heart disease is a major cause of death in the Western societies. One of the most promising interventions to prevent and slow down the progress of coronary heart disease is the elevation of high density lipoprotein (HDL) levels in circulation. Animal models together with early clinical studies have shown that the inhibition of cholesteryl ester transfer protein (CETP) is a promising strategy to achieve higher HDL levels. However, drugs with acceptable side-effects for CETP-inhibition do not yet exist, although the next generation CETP inhibitor (anacetrapib) has great potential in this regard. In this study, our objective is to gain more detailed information regarding the interactions of CETP with lipoprotein particles. We show how the CETP-lipoprotein complex is formed and how lipid exchange between CETP and lipoprotein particles takes place. Our findings help to understand in a mechanistic way how CETP-mediated lipid exchange occurs and how it could be exploited in the design of new and more efficient molecular agents against coronary heart disease.
PMCID: PMC3257282  PMID: 22253581
3.  High Density Lipoprotein Structural Changes and Drug Response in Lipidomic Profiles following the Long-Term Fenofibrate Therapy in the FIELD Substudy 
PLoS ONE  2011;6(8):e23589.
In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.
PMCID: PMC3160907  PMID: 21887280
4.  Association of Lipidome Remodeling in the Adipocyte Membrane with Acquired Obesity in Humans 
PLoS Biology  2011;9(6):e1000623.
The authors describe a new approach to studying cellular lipid profiles and propose a compensatory mechanism that may help maintain the normal membrane function of adipocytes in the context of obesity.
Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.
Author Summary
Obesity is characterized by excess body fat, which is predominantly stored in the adipose tissue. When adipose tissue expands too much it stops storing lipid appropriately. The excess lipid accumulates in organs such as muscle, liver, and pancreas, causing metabolic disease. In this study, we aim to identify factors that cause adipose tissue to malfunction when it reaches its limit of expansion. We performed lipidomic analyses of human adipose tissue in twin pairs discordant for obesity—that is, one of the twins was lean and one was obese—but still metabolically healthy. We identified multiple changes in membrane phospholipids. Using computer modeling, we show that “lean” and “obese” membrane lipid compositions have the same physical properties despite their different compositions. We hypothesize that this represents allostasis—changes in lipid membrane composition in obesity occur to protect the physical properties of the membranes. However, protective changes cannot occur without a cost, and accordingly we demonstrate that switching to the “obese” lipid composition is associated with higher levels of adipose tissue inflammation. In a separate group of metabolically unhealthy obese individuals we investigated how the processes that regulate the “lean” and “obese” lipid profiles are changed. To determine how these lipid membrane changes are regulated we constructed an in silico network model that identified key control points and potential molecular players. We validated this network by performing genetic manipulations in cell models. Therapeutic targeting of this network may open new opportunities for the prevention or treatment of obesity-related metabolic complications.
PMCID: PMC3110175  PMID: 21666801
5.  Role of Lipids in Spheroidal High Density Lipoproteins 
PLoS Computational Biology  2010;6(10):e1000964.
We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules surrounding the lipid compartment. The present models are the first ones among computational studies where the size and lipid composition of HDL are realistic, corresponding to human serum HDL. We focus on the role of lipids in HDL structure and dynamics. Particular attention is paid to the assembly of lipids and the influence of lipid-protein interactions on HDL properties. We find that the properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). Unlike the hydrophobic core, the intermediate and surface regions are characterized by prominent conformational lipid order. Yet, not only the conformations but also the dynamics of lipids are found to be distinctly different in the different regions of HDL, highlighting the importance of dynamics in considering the functionalization of HDL. The structure of the lipid droplet close to the HDL-water interface is altered by the presence of apoA-Is, with most prominent changes being observed for cholesterol and polar lipids. For cholesterol, slow trafficking between the surface layer and the regimes underneath is observed. The lipid-protein interactions are strongest for cholesterol, in particular its interaction with hydrophobic residues of apoA-I. Our results reveal that not only hydrophobicity but also conformational entropy of the molecules are the driving forces in the formation of HDL structure. The results provide the first detailed structural model for HDL and its dynamics with and without apoA-I, and indicate how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly.
Author Summary
Cardiovascular diseases are the primary cause of death in western countries. One of the main causes is lipid accumulation and plaque formation on arterial walls, called atherosclerosis. The risk of being exposed to this condition is reduced by high levels of high density lipoprotein (HDL). The functionality of HDL has remained elusive, and even its structure is not well understood. Through extensive coarse-grained simulations, we have clarified the structure of the lipid droplet in HDL and elucidated its interactions with the apolipoprotein A-I (apoA-I) that surrounds the droplet. We have found that the structural and dynamic properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). As for apoA-I, we have observed it alter the overall structure of the lipid droplet close to the HDL-water interface, with prominent changes taking place for cholesterol and other polar lipids. The nature of lipid-protein interactions is most favorable for cholesterol. Our results reveal that not only hydrophobicity but also conformational entropy are the driving forces in the formation of HDL structure, suggesting how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly.
PMCID: PMC2965744  PMID: 21060857
6.  Cholesterol Induces Specific Spatial and Orientational Order in Cholesterol/Phospholipid Membranes 
PLoS ONE  2010;5(6):e11162.
In lipid bilayers, cholesterol facilitates the formation of the liquid-ordered phase and enables the formation of laterally ordered structures such as lipid rafts. While these domains have an important role in a variety of cellular processes, the precise atomic-level mechanisms responsible for cholesterol's specific ordering and packing capability have remained unresolved.
Methodology/Principal Findings
Our atomic-scale molecular dynamics simulations reveal that this ordering and the associated packing effects in membranes largely result from cholesterol's molecular structure, which differentiates cholesterol from other sterols. We find that cholesterol molecules prefer to be located in the second coordination shell, avoiding direct cholesterol-cholesterol contacts, and form a three-fold symmetric arrangement with proximal cholesterol molecules. At larger distances, the lateral three-fold organization is broken by thermal fluctuations. For other sterols having less structural asymmetry, the three-fold arrangement is considerably lost.
We conclude that cholesterol molecules act collectively in lipid membranes. This is the main reason why the liquid-ordered phase only emerges for Chol concentrations well above 10 mol% where the collective self-organization of Chol molecules emerges spontaneously. The collective ordering process requires specific molecular-scale features that explain why different sterols have very different membrane ordering properties: the three-fold symmetry in the Chol-Chol organization arises from the cholesterol off-plane methyl groups allowing the identification of raft-promoting sterols from those that do not promote rafts.
PMCID: PMC2887443  PMID: 20567600
7.  Conformational Changes and Slow Dynamics through Microsecond Polarized Atomistic Molecular Simulation of an Integral Kv1.2 Ion Channel 
PLoS Computational Biology  2009;5(2):e1000289.
Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins—not to mention numerous applications in drug design. Here, we present a full 1 µs atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120° rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation (∼35°) of the extracellular end of all S4 segments is present also in a reference 0.5 µs simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 310 helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4–lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5–1 µs). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.
Author Summary
Proteins that transport ions across the cellular membrane are essential for cellular life. The proteins conducting positively charged potassium ions are key players in heart beat and nerve impulse generation because they are regulating the electrical excitability of the cell (together with proteins transporting other ions). These particular ion channels open and close in response to voltage changes across cellular membranes, but the details of this process are still not fully understood. It is, however, known that the main protein element responsible is a helical section containing several charges. Through new computer simulation methods, we have been able to run unprecedentedly long atomic simulations of an entire potassium channel embedded within a patch of membrane to help to shed new light on this gating process. Upon changing the voltage across the membrane, we observe a change in structure of this helical protein segment that appears to be an early sign of transition from the open to the closed state of the channel. This has also been previously proposed to be critical for the gating process. Understanding these structural changes on an atomic level is essential for both advancing basic science and enabling drug design targeting of voltage-regulated ion channels.
PMCID: PMC2632863  PMID: 19229308
8.  Assessing the Nature of Lipid Raft Membranes 
PLoS Computational Biology  2007;3(2):e34.
The paradigm of biological membranes has recently gone through a major update. Instead of being fluid and homogeneous, recent studies suggest that membranes are characterized by transient domains with varying fluidity. In particular, a number of experimental studies have revealed the existence of highly ordered lateral domains rich in sphingomyelin and cholesterol (CHOL). These domains, called functional lipid rafts, have been suggested to take part in a variety of dynamic cellular processes such as membrane trafficking, signal transduction, and regulation of the activity of membrane proteins. However, despite the proposed importance of these domains, their properties, and even the precise nature of the lipid phases, have remained open issues mainly because the associated short time and length scales have posed a major challenge to experiments. In this work, we employ extensive atom-scale simulations to elucidate the properties of ternary raft mixtures with CHOL, palmitoylsphingomyelin (PSM), and palmitoyloleoylphosphatidylcholine. We simulate two bilayers of 1,024 lipids for 100 ns in the liquid-ordered phase and one system of the same size in the liquid-disordered phase. The studies provide evidence that the presence of PSM and CHOL in raft-like membranes leads to strongly packed and rigid bilayers. We also find that the simulated raft bilayers are characterized by nanoscale lateral heterogeneity, though the slow lateral diffusion renders the interpretation of the observed lateral heterogeneity more difficult. The findings reveal aspects of the role of favored (specific) lipid–lipid interactions within rafts and clarify the prominent role of CHOL in altering the properties of the membrane locally in its neighborhood. Also, we show that the presence of PSM and CHOL in rafts leads to intriguing lateral pressure profiles that are distinctly different from corresponding profiles in nonraft-like membranes. The results propose that the functioning of certain classes of membrane proteins is regulated by changes in the lateral pressure profile, which can be altered by a change in lipid content.
Author Summary
Biological membranes are complex 2-D assemblies of various lipid species and membrane proteins. For long, it was thought that the main role of lipid membranes is to provide a homogeneous, liquid-like platform for membrane proteins to carry out their functions as they diffuse freely in the membrane plane. Recently, that view has changed. It has become evident that several lipid environments with different physical properties may coexist, and that the properties of the different lipid domains may play an active role in regulating the conformational state and dynamic sorting of membrane proteins. We have carried out atom-scale computer simulations for three-component lipid bilayers, so-called lipid rafts, rich in cholesterol and sphingolipids. They show that arising from the local interactions between the lipid species, the elastic and dynamic properties of the membranes depend strongly on the lipid composition. The changes in elastic properties are suggested to alter the functional states of various membrane proteins. Changes in lipid composition are also shown to alter the distribution of local pressure inside the membrane. This is likely to affect proteins that undergo large anisotropic conformational changes between the functional states, such as the ion channel MscL, used as an example here. A great number of important physiological phenomena, such as transmitting neural impulses or trafficking molecules in and out of the cell, involve activation of membrane proteins, so it is relevant to understand all factors affecting them. Our findings support the idea that general physical properties of the lipid environment are capable of regulating membrane proteins.
PMCID: PMC1808021  PMID: 17319738

Results 1-8 (8)