Conjugated double bonds in lipid bilayers: a molecular dynamics simulation study

Conjugated linoleic acids (CLA) are found naturally in dairy products. Two isomers of CLA, that differ only in the location of cis and trans double bonds, are found to have distinct and different biological effects. The cis 9 trans 11 (C9T11) isomer is attributed to have the anti-carcinogenic effects, while the trans 10 cis 12 (T10C12) isomer is believed to be responsible for the anti-obesity effects. Since dietary CLA are incorporated into membrane phospholipids, we have used Molecular Dynamics (MD) simulations to investigate the comparative effects of the two isomers on lipid bilayer structure. Specifically, simulations of phosphatidylcholine lipid bilayers in which the sn-2 chains contained one of the two isomers of CLA were performed. Force field parameters for the torsional potential of double bonds were obtained from ab initio calculations. From the MD trajectories we calculated and compared structural properties of the two lipid bilayers, including areas per molecule, density profiles, thickness of bilayers, tilt angle of tail chains, order parameters profiles, radial distribution function (RDF) and lateral pressure profiles. The main differences found between bilayers of the two CLA isomers, are (1) the order parameter profile for C9T11 has a dip in the middle of sn-2 chain while the profile for T10C12 has a deeper dip close to terminal of sn-2 chain, and (2) the lateral pressure profiles show differences between the two isomers. Our simulation results reveal localized physical structural differences between bilayers of the two CLA isomers that may contribute to different biological effects through differential interactions with membrane proteins or cholesterol.     

Lipid Membrane Structure and Dynamics Studied by All-Atom Molecular Dynamics Simulations of Hydrated Phospholipid Bilayers

Abstract

The structure and dynamics of phosphatidylcholine bilayers are examined by reviewing the results of several nanoseconds of molecular dynamics simulations on a number of bilayer and monolayer models. The lengths of these simulations, the longest single one of which was 2 nanoseconds, were sufficiently long to effectively sample many of the longer-scale motions governing the behaviour of biomembranes. These simulations reproduce many experimental observables well and provide a degree of resolution currently unavailable experimentally.     

Simulating realistic membrane shapes

Biological membranes exhibit diversity in their shapes and complexity in chemical compositions that are linked to many cellular functions. These two central features of biomembranes have been the subject of numerous simulation studies, using a diverse range of computational techniques. Currently, the field is able to capture this complexity at increasing levels of realism and connect the microscopic view on protein–lipid interactions to cellular morphologies at the level of entire organelles. Here we highlight recent advances in this topic, identify current bottlenecks, and sketch possible ways ahead.     

Molecular dynamics study of enhanced autophosphorylation by S904F mutation of the RET kinase domain

The aberrant kinase activity of RET (rearranged during transfection), a transmembrane tyrosine kinase, is associated with human cancer. A point mutation caused by the replacement of solvent-front hydrophilic S904, located on the activation loop (A-loop), with a bulky hydrophobic phenylalanine residue can induce resistance to the type I kinase inhibitor vandetanib. A possible mechanism of this drug resistance is the release of a cis-autoinhibited conformation of RET for autophosphorylation, which activates RET kinase. Because the association between S904F mutation and enhanced autophosphorylation is unclear, we conducted molecular modeling analysis to compare unphosphorylated apo wild-type and S904F mutant structures. The structural compactness of the A-loop promoted ATP binding. When the A-loop is extended, the αC helix moves toward the glycine-rich loop, resulting in the protrusion of F735. The extruded F735 connects with E734 and R912 and constrains the ATP pocket entrance. Contrarily, a contracted A-loop pulls the αC helix away from the glycine-rich loop, burying F734 and making the ATP pocket accessible. The mutated F904 stabilizes the contracted A-loop and releases the autoinhibited conformation of RET, thereby facilitating autophosphorylation. We also simulated two ATP-bound systems. The binding free energies of ATP, estimated through the molecular mechanics with a generalized Born and surface area solvation approach, revealed that the S904F mutant was bound more tightly than was the wild type with the ATP. The findings support the premise of autophosphorylation promotion in the S904F mutant.     

Molecular dynamics study of methane in water: diffusion and structure

In this study, theoretical analysis on the geometries and electronic properties of various conjugated oligomers based on thiophene (Th) or bicyclic non-classical Th units is reported. The dihedral angle, bond length, bond-length alternation, bond critical point (BCP) properties, nucleus-independent chemical shift (NICS) and Wiberg bond index (WBIs) are analysed and correlated with conduction properties. The changes of bond length, BCP properties, NICS and WBIs all show that the conjugational degree is increased systematically with main chain extension. As a result, the highest occupied molecular orbital–lowest unoccupied molecular orbital energy separation (E _g) is decreased upon chain elongation. The E _g of oligomers based on bicyclic non-classical Th unit is much lower than that of Th-based oligomers due to the narrower E _g of bicyclic non-classical Ths compared to Th, which indicates that the narrow E _g of the bicyclic non-classical Ths can be carried over to their polymers by using them as building blocks for the polymers. The band structures and density of states analysis show that the four polymers all have small band gap ( < 0.9 eV), wide highest occupied bandwidth and relatively small effective mass of hole, which indicate that those proposed polymers may be potential conductors.     

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.     

Coarse-grained molecular dynamics simulations of membrane proteins and peptides

Molecular dynamics (MD) simulations provide a valuable approach to the dynamics, structure, and stability of membrane-protein systems. Coarse-grained (CG) models, in which small groups of atoms are treated as single particles, enable extended (>100 ns) timescales to be addressed. In this study, we explore how CG-MD methods that have been developed for detergents and lipids may be extended to membrane proteins. In particular, CG-MD simulations of a number of membrane peptides and proteins are used to characterize their interactions with lipid bilayers. CG-MD is used to simulate the insertion of synthetic model membrane peptides (WALPs and LS3) into a lipid (PC) bilayer. WALP peptides insert in a transmembrane orientation, whilst the LS3 peptide adopts an interfacial location, both in agreement with experimental biophysical data. This approach is extended to a transmembrane fragment of the Vpu protein from HIV-1, and to the coat protein from fd phage. Again, simulated protein/membrane interactions are in good agreement with solid state NMR data for these proteins. CG-MD has also been applied to an M3-M4 fragment from the CFTR protein. Simulations of CFTR M3-M4 in a detergent micelle reveal formation of an alpha-helical hairpin, consistent with a variety of biophysical data. In an I231D mutant, the M3-M4 hairpin is additionally stabilized via an inter-helix Q207/D231 interaction. Finally, CG-MD simulations are extended to a more complex membrane protein, the bacterial sugar transporter LacY. Comparison of a 200 ns CG-MD simulation of LacY in a DPPC bilayer with a 50 ns atomistic simulation of the same protein in a DMPC bilayer shows that the two methods yield comparable predictions of lipid-protein interactions. Taken together, these results demonstrate the utility of CG-MD simulations for studies of membrane/protein interactions.     

A molecular-dynamics simulation study of diffusion of a single model carbonic chain on a graphite (001) surface

Molecular-dynamics simulations have been used to study the diffusion of a short single model carbonic chain on the graphite (001) surface. The calculated diffusion coefficient (D) first increases, then decreases with increasing chain length (N). This abnormal behavior is similar to polymer lateral diffusion at the solid–liquid interface. Furthermore, we have studied the relation between the mean-square gyration radius and N. Figure Log–log plot of the self-diffusion coefficient D versus the chain length N. The error bars are the standard deviation measured in three repeated simulations     

KcsA closed and open: modelling and simulation studies

Bacterial homologues of mammalian potassium channels provide structures of two states of a gated K channel. Thus, the crystal structure of KcsA represents a closed state whilst that of MthK represents an open state. Using homology modelling and molecular dynamics simulations we have built a model of the transmembrane domain of KcsA in an open state and have compared its conformational stability with that of the same domain of KcsA in a closed state. Approximate Born energy calculations of monovalent cations within the two KcsA channel states suggest that the intracellular hydrophobic gate in the closed state provides a barrier of height ~5 kT to ion permeation, whilst in the open state the barrier is absent. Simulations (10 ns duration) in an octane slab (a simple membrane mimetic) suggest that closed- and open-state models are of comparable conformational stability, both exhibiting conformational drifts of ~3.3 Å C RMSD relative to the respective starting models. Substantial conformational fluctuations are observed in the intracellular gate region during both simulations (closed state and open state). In the simulation of open-state KcsA, rapid (<5 ns) exit of all three K⁺ ions occurs through the intracellular mouth of the channel. Helix kink and swivel motion is observed at the molecular hinge formed by residue G99 of the M2 helix. This motion is more substantial for the open- than for the closed-state model of the channel.     

A Molecular Dynamics Study of Human Defensins HBD-1 and HNP-3 in Water

Abstract

Mammalian defensins are crucial components of the innate immune system. They are characterized by three disulfide bridges and exhibit broad spectrum antibacterial activity. The spacing between the cysteines and disulfide connectivities in the two classes of defensins, the α- and β-forms, are different. The structural motif of 3 β-strands appears to be conserved in α and β-defensins despite differences in disulfide connectivities and spacing between cysteines. In this study, Molecular Dynamics Simulations (MDS) have been carried out to study the conformational behavior of α- and β-defensins with and without disulfide bridges. Our results indicate that β-strands in the C-terminal region of HBD-1 and HNP-3 do not unfold during the course of MDS. The segment adopting α-helix in HBD-1 unfolds early during the simulations. The backbone hydrogen bonds in HBD-1 and HNP-3 are broken during MDS. When the disulfide bonds are absent, the N-terminal β-strand unfolds by 20 ns but β-strands are observed in the C-terminal region of HNP-3. HBD-1, without disulfide bridges, unfolds to a greater extent during the course of the MDS. Examination of distances between sulfur atoms of cysteines without disulfide bridges during the simulations indicate that there is no specific preference for native disulfide bridges, which could be the reason for the experimental observation of non-native disulfide bridge formation during chemical synthesis of human α- and β-defensins. Since defensins with non-native disulfide bridges are biologically active, the exact three dimensional structures observed for native HBD-1 and HNP-3 does not appear to be essential for exhibiting antibacterial activity.     

Molecular dynamics study of the conformational stability of esterase 2 from Alicyclobacillus acidocaldarius

Circular dichroism and differential scanning calorimetry measurements showed that esterase 2 from the thermophilic microorganism Alicyclobacillus acidocaldarius, EST2, and its variant in which the first 35 residues have been deleted, EST2-36del, unfold reversibly on increasing temperature, and possess two cooperative and coupled domains [12]. Structural features of the α/β hydrolase fold of EST2, with nine α-helices packed against the central twisted β-sheet, do not allow a straightforward identification of these two cooperative and coupled domains. Molecular dynamics simulations, each one 20 ns long, have been performed at 300, 400 and 500 K, on both proteins in explicit water. Suitable analysis of MD trajectories has allowed a reliable identification of the two cooperative domains (i.e., the less stable one corresponds to external α-helices, whereas the more stable one corresponds to the central twisted β-sheet) and the attribution of the key coupling role to the last and long α-helix of EST2.     

Effects of deformability and thermal motion of lipid membrane on electroporation: by molecular dynamics simulations

Effects of mechanical properties and thermal motion of POPE lipid membrane on electroporation were studied by molecular dynamics simulations. Among simulations in which specific atoms of lipids were artificially constrained at their equilibrium positions using a spring with force constant of 2.0 kcal/(mol Ų) in the external electric field of 1.4 kcal/(mol Å e), only constraint on lateral motions of lipid tails prohibited electroporation while non-tail parts had little effects. When force constant decreased to 0.2 kcal/(mol Ų) in the position constraints on lipid tails in the external electric field of 2.0 kcal/(mol Å e), water molecules began to enter the membrane. Position constraints of lipid tails allow water to penetrate from both sides of membrane. Thermal motion of lipids can induce initial defects in the hydrophobic core of membrane, which are favorable nucleation sites for electroporation. Simulations at different temperatures revealed that as the temperature increases, the time taken to the initial pore formation will decrease.     

Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1 (GGTase1) and Farnesyl Transferase (FTase)

Protein prenylation is a posttranslational modification that is indispensable for translocation of membrane GTPases like Ras, Rho,Ras etc. Proteins of Ras family undergo farnesylation by FTase while Rho family goes through geranylgeranylation by GGTase1.There is only an infinitesimal difference in signal recognition between FTase and GGTase1. FTase inhibitors mostly end upselecting the cells with mutated Ras proteins that have acquired affinity towards GGTase1 in cancer microcosms. Therefore, it is ofinterest to identify GGTase1 and FTase dual inhibitors using the docking tool AutoDock Vina. Docking data show that curcumin(from turmeric) has higher binding affinity to GGTase1 than that of established peptidomimetic GGTase1 inhibitors (GGTI) such asGGTI-297, GGTI-298, CHEMBL525185. Curcumin also interacts with FTase with binding energy comparable to co-crystalizedcompound 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(1-methyl-1h-imidizol-5-yl)-ethyl]-benzonitrile (BNE).The docked complex was further simulated for 10 ns using molecular dynamics simulation for stability. Thus, the molecular basisfor curcumin binding to GGTase1 and FTase is reported.     

Molecular dynamics (MD) simulations for the prediction of chiral discrimination of N-acetylphenylalanine enantiomers by cyclomaltoheptaose (beta-cyclodextrin, beta-CD) based on the MM-PBSA (molecular mechanics-Poisson-Boltzmann surface area) approach

Molecular dynamics (MD) simulations were performed for the prediction of chiral discrimination of N-acetylphenylalanine enantiomers by cyclomaltoheptaose (beta-cyclodextrin, beta-CD). Binding free energies and various conformational properties were obtained using by the MM-PBSA (molecular mechanics Poisson-Boltzmann/surface area) approach. The calculated relative difference (DeltaDeltabinding) of binding free energy was in fine agreement with the experimentally determined value. The difference of rotameric distributions of guest N-acetylphenylalanine enantiomers complexed with the host, beta-CD, was observed after the conformational analyses, suggesting that the conformational changes of guest captured within host cavity would be a decisive factor for enantiodifferentiation at a molecular level.     

Molecular modeling studies of atorvastatin analogues as HMGR inhibitors using 3D-QSAR,molecular docking and molecular dynamics simulations

3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) is generally regarded as targets for the treatment of hypercholesterolemia. HMGR inhibitors (more commonly known as statins) are discovered as plasma cholesterol lowering molecules. In this work, 120 atorvastatin analogues were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q² = 0.558 and r² = 0.977, and the best CoMSIA (comparative molecular similarity indices analysis) model has q² = 0.582 and r² = 0.919. Molecular docking and MD simulation explored the binding relationship of the ligand and the receptor protein. The calculation results indicated that the hydrophobic and electrostatic fields play key roles in QSAR model. After MD simulation, we found four vital residues (Lys735, Arg590, Asp690 and Asn686) and three hydrophobic regions in HMGR binding site. The calculation results show that atorvastatin analogues obtained by introduction of F atoms or gem-difluoro groups could obviously improve the inhibitory activity. The new HMGR inhibitor analogues design in this Letter had been submitted which is being currently synthesized by our laboratories.     

Molecular dynamics simulation of polyelectrolyte with oppositely charged monomeric and dimeric surfactants

Interactions of anionic polyelectrolyte (PE) with cationic monomeric (MS) and dimeric surfactants (DS) have been investigated by coarse-grained molecular dynamics (MD) simulation. A PE/surfactant mixture is observed to evolve over time into micellar complex of increasing size. The critical aggregation concentration (CAC) is qualitatively found to be much lower than the critical micellization concentration (CMC) of the free surfactant. Compared to the monomeric analog, a DS interacts more strongly with the oppositely charged polyion chain. The equilibrium complex size becomes larger with increasing surfactant concentration. Simulation results are consistent with experimental observations and reveal that the electrostatic and hydrophobic interactions play an important role in the formation of micellar complex.     

Molecular simulation on the interaction of Ethinylestradiol (EE2) with polymer membranes in wastewater purification

Molecular dynamics (MD) simulations are performed to study the adsorption of solute organic molecules (Ethinylestradiol (EE2) and testosterone) with different polymer membranes such as polyether sulfone (PES), polyvinylidene fluoride (PVDF). The equilibrium MD simulations results for the membrane solution interface system show that the interaction of EE2 with PES is specific and strong, whereas the interaction is weak and non-specific for PVDF. The binding free energies, the non-bonded short range interaction energies and mobility are also consistent with the interaction behaviour found in experiments. The adsorption of testosterone onto PES and PVDF is considered as control system. The result shows that binding free energies of PES and PVDF interacting with organic solute are consistent with experimental result in the order as; PES-EE2 > PES-Testosterone > PVDF-EE2 > PVDF-Testosterone. The formation hydrogen bonds and π–π interactions are observed between the EE2 and PES. In addition, adsorption of EE2 onto polyamide 6-12 (PA612) and polystyrene (PS) membranes are predicted. This simulation study provides molecular insights on the experimental observations and helps as a computational methodology to screen the membrane materials for EE2 removal from wastewater.     

Molecular dynamics simulation of energetic uranium recoil damage in zircon

Defect production and amorphisation due to energetic uranium recoils in zircon (ZrSiO₄), which is a promising ceramic nuclear waste form, is studied using molecular dynamics (MD) simulations with a partial charge model. An algorithm that distinguishes between undamaged crystal, crystalline defects and amorphous regions is used to develop a fundamental understanding of the primary damage state. The amorphous cascade core is separated from the surrounding crystal by a defect-rich region. Small, chemically inhomogeneous amorphous clusters are also produced around the core. The amorphous regions consist of under-coordinated Zr and polymerised Si leading to amorphisation and phase separation on a nanometer scale into Zr- and Si-rich regions. This separation could play an important role in the experimentally observed formation of nanoscale ZrO₂ in ZrSiO₄ irradiated at elevated temperatures.     

Molecular dynamics simulations and MM/GBSA methods to investigate binding mechanisms of aminomethylpyrimidine inhibitors with DPP-IV

The aminomethylpyrimidines were investigated as a novel class of DPP-IV inhibitors. In this Letter, the binding mechanisms of how slight change of substitution or position influences the binding affinity of five representative analogs was investigated by molecular dynamics simulation, free energy calculations and energy decomposition analysis. The conserved hydrogen bonds with Glu205 and Glu206 slightly favor the inhibitor binding; the van der Waals interactions, especially the two key contacts with Tyr547 and Tyr666, dominate in the binding free energy and play a crucial role on distinguishing the high active inhibitors from the low ones.