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Multinanosecond molecular dynamics (MD) simulations have been employed to characterize the interaction of an integral membrane protein (IMP), the leucine transmitter from Aquifex aeolicus(Yamashita et al., Nature2005, 437, 215−223), with hydrated lipid bilayer membranes in their physiologically relevant liquid crystalline phases. Analysis of the MD trajectories for dimyristoyl phosphatidylcholine (DMPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), and 1-palmitoyl-2-oleoyl phosphatidylethanolamine (POPE) focused on the contacts between aromatic and basic side chains of the IMP with the lipid head groups and water. Structural fluctuations of the IMP were investigated as well as the contact dynamics of neighboring lipids. In characterizing the IMP−membrane systems, the behaviors of the protein’s cytoplasmic and periplasmic parts are considered separately. All three lipid membranes show a rather similar overall level of association with the IMP. However, for DMPC there is a better matching of the membrane core to the hydrophobic transmembrane portion of the IMP. The closed cytoplasmic end of the IMP exhibits a higher degree of association with lipids than the more open periplasmic end, an observation which correlates with the more compact structure and a slower dynamics of surrounding lipids. [ABSTRACT FROM AUTHOR]

The structure of an aqueous 1-n-decyl-3-methylimidazolium bromide solution and its vapor−liquid interface has been studied using molecular dynamics (MD) simulations. Starting from an isotropic solution, spontaneous self-assembly of cations into small micellar aggregates has been observed. The decyl chains are buried inside the micelle to avoid unfavorable interactions with water, leaving the polar headgroups exposed to water. The cation aggregation numbers, ranging from 15 to 24 compare favorably with experimental estimates. Results are presented for the organization of solvent around the cations. The structure of the aggregates as determined from the present MD simulations does not support the staircase model proposed on the basis of nuclear magnetic resonance studies on similar aqueous ionic-liquid solutions. The distribution of ions in bulk solutions and at an air/water interface is also discussed. [ABSTRACT FROM AUTHOR]

Using first principles molecular dynamics simulation, we have studied a fluoride anion embedded in a periodically replicated water slab composed of 215 water molecules to mimic both bulk and interfacial solvation. In contrast to some recent experiments, our findings suggest that there are only small structural changes for fluoride and its first solvation shell in the bulk. Moreover, the presence of fluoride does not significantly alter the rotational dynamics of nearby water. In addition, we have computed the molecular dipole moments using Wannier centers. At the interface, the presence of fluoride increases the molecular dipole moments of nearby water molecules, whereas in the bulk, the dipole moments for water appear to be essentially invariant to the presence of fluoride in the vicinity. Previous studies of the air−water interface have showed interfacial water to have higher average HOMO energies and, thus, likely to be more prone to electrophilic attack. With the addition of fluoride, the most likely reactive site for electrophilic reactions shifts to the anion. This finding could explain the known large increase in reaction rates for heterogeneous process of interest in atmospheric science. The reactive properties of other anions near the air−water interface are of general interest in heterogeneous chemistry and can be elucidated using a similar type of analysis, as performed here for the fluoride anion. [ABSTRACT FROM AUTHOR]

Self-assembly of a nanotube forming molecule, hexa-peri-hexabenzocoronene (hbc), in aqueous solution is studied using a coarse-grain (CG) force-field in molecular dynamics (MD) simulations. The simulations yield details of the pre-aggregation regime, which is generally inaccessible to experimental studies. The simulations also provide insights into the self-assembly mechanism, revealing how the aggregates formed in the initial stages of self-assembly grow in size to form a columnar structure. At later stages self-organization results in the formation of a twisted ribbon-like structure that remains stable for the duration of the simulation. This twisted ribbon-like structure is probably an intermediate in the formation of a nanotubular object. [ABSTRACT FROM AUTHOR]

Despite the widespread clinical use of anesthetics since the 19th century, a clear understanding of the mechanism of anesthetic action has yet to emerge. On the basis of early experiments by Meyer, Overton, and subsequent researchers, the cell’s lipid membrane was generally concluded to be the primary site of action of anesthetics. However, later experiments with lipid-free globular proteins, such as luciferase and apoferritin, shifted the focus of anesthetic action to proteins. Recent experimental studies, such as photoaffinity labeling and mutagenesis on membrane proteins, have suggested specific binding sites for anesthetic molecules, further strengthening the proteocentric view of anesthetic mechanism. With the increased availability of high-resolution crystal structures of ion channels and other integral membrane proteins, as well as the availability of powerful computers, the structure−function relationship of anesthetic-protein interactions can now be investigated in atomic detail. [ABSTRACT FROM AUTHOR]

Room temperature ionic liquids (IL) composed of organic cations and inorganic anions are already being utilized for wide-ranging applications in chemistry. Complementary to experiments, computational modelling has provided reliable details into the nature of their interactions. The intra- and intermolecular structures, dynamic and transport behaviour and morphologies of these novel liquids have also been explored using simulations. The current status of molecular modelling studies is presented along with the prognosis for future work in this area. [ABSTRACT FROM AUTHOR]

DNA−carbon nanotube hybrids (DNA−CN) are novel nanoscale materials that consist of single-wall carbon nanotubes (SWCN) coated with a self-assembled monolayer of single-stranded DNA (ssDNA). Recent experiments on DNA−CN have shown that this material offers a remarkable set of technologically useful properties such as facilitation of SWCN sorting, chemical sensing, and detection of DNA hybridization. Despite the importance of DNA−CN, a detailed understanding of its microscopic structure and physical properties is lacking. To address this, we have performed classical all-atom molecular dynamics (MD) simulations exploring the self-assembly mechanisms, structure, and energetic properties of this nanomaterial. MD reveals that SWCN induces ssDNA to undergo a spontaneous conformational change that enables the hybrid to self-assemble via the − stacking interaction between ssDNA bases and SWCN sidewall. ssDNA is observed to spontaneously wrap about SWCN into compact right- or left-handed helices within a few nanoseconds. Helical wrapping is driven by electrostatic and torsional interactions within the sugar−phosphate backbone that result in ssDNA wrapping from the 3‘ end to the 5‘ end. [ABSTRACT FROM AUTHOR]

The Zr4tetramer, Zr4(OH)8(H2O)168, is thought to be the major component of the Zr4polymer system in aqueous solution, present as a dominant ionic cluster species compared to other Zr4clusters under various experimental conditions. Despite widespread applications of zirconium, the structure and dynamics of the tetramer in aqueous solution are not well understood. We conducted a combination of ab initio molecular dynamics and quantum mechanical studies in the gas phase and aqueous solution and related our results to the available experimental data to provide atom-level information on the behavior of this species in aqueous solution. Our simulations indicate that the tetramer structure is stable on the picosecond time scale in an aqueous environment and that it is of a planar form, comprising eight-coordinated Zr4ions with an antiprism/irregular dodecahedron ligand arrangement. In combination with our studies of Zr4dimer and trimer clusters, our results provide detailed geometrical information on structural motifs for building zirconium polymers and suggest a possible polymerization path. [ABSTRACT FROM AUTHOR]

2-Aminoethoxydiphenylborate(2-APB) is a broad-spectrum modulatorof various membrane proteins. Specifically, it exhibits concentrationdependent modulation of calcium signaling through store-operated calcium(SOC) channels: low micromolar concentration of 2-APB stimulates SOCentry while a higher concentration induces complete inhibition. Abinitio quantum chemical calculations show that the relative stabilityof the two major isomers of 2-APB (cyclic and extended) is about 8kcal/mol. The dual functionality of 2-APB for SOC channels is thuslikely associated with its ability to switch among isomeric forms,suited to different binding sites in the SOC channels with distinctbinding affinities. Importantly, the moderate relative stability ofdifferent isomers results from a delicate balance between the intramolecularboron–nitrogen coordinate bond with strength about −45kcal/mol and ring strain engendered by cyclic oligomerization. Thesynergistic effect of these two factors likely makes 2-APB an idealdual effect drug. [ABSTRACT FROM AUTHOR]

Recently, we reported new coarse grain (CG) force fields for lipids and phenyl/fullerene based molecules. Here, we developed the cross parameters necessary to unite those force fields and then applied the model to investigate the nature of benzene and C60interactions with lipid bilayers. The interaction parameters between the phenyl and lipid CG sites are based on experimental and all atom (AA) molecular dynamics (MD) data. The resulting force field was tested on benzene rich lipid bilayers and shown to reproduce general behavior expected from experiments. The parameters were then applied to C60interactions with lipid bilayers. Overall, the results showed excellent agreement with AA MD and experimental observations. In the C60lipid systems, the fullerenes were shown to aggregate even at the lowest concentrations investigated. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations with the CHARMM atomistic force field have been used to study monolayers of a series of linear alkylbenzene sulfonates (LAS) at the water/air interface. Both the numbers of carbon atoms in the LAS alkyl tail (1 to 11) and the position of attachment of the benzene ring on the alkyl chain have been varied. Totally 36 LAS homologues and isomers have been investigated. The surface tensions of the systems and the average tilt angles of the LAS molecules are found to be related to both the length and the degree of branching of the alkyl tails, whereas the solubility and mobility are mostly determined by the tail length. [ABSTRACT FROM AUTHOR]

Combining single-walled carbon nanotubes (CNT) with biological molecules provides a route to novel nanoscale materials with many promising applications in nanotechnology and nanomedicine. Recent experiments show that CNTs covalently functionalized with the coxsackie-adenovirus receptor (CAR) serve as biosensors capable of specifically recognizing Knob proteins from the adenovirus capsid. These experiments suggest that CAR retains its biologically active form when bound to CNT, but a detailed understanding of the structural changes that occur within CAR after CNT attachment is lacking. To address this, we have performed all-atom classical molecular dynamics (MD) simulations of CAR and the CAR-Knob complex in aqueous solution alone and also when covalently linked to CNT. The MD results show that the CNT damps structural fluctuations in CAR and reduces the internal mobility of the protein. However, CNT induces very little structural deformation and does not affect CAR’s ability to specifically bind Knob. This MD study verifies that CAR retains its biological functionality when attached to CNT and provides a computational approach to rationalize nanobiosensing devices. [ABSTRACT FROM AUTHOR]

The DNA−carbon nanotube hybrid (DNA-CN) consists of a single-wall carbon nanotube (SWCN) coated with a self-assembled monolayer of single-stranded DNA (ssDNA). Recent experiments have demonstrated that this nanomaterial is ideal for numerous nanotechnological applications. Despite this importance, the structure of this material remains poorly understood. Molecular dynamics (MD) simulations have provided information about the self-assembly mechanisms and ssDNA conformations that characterize DNA-CN. However, MD simulations of biopolymers at low temperatures (T∼ 300 K) result in kinetic trapping that limits conformational sampling. Here, we present results of a large-scale replica exchange molecular dynamics (REMD) simulation that provides extensive sampling of the entire ensemble of oligonucleotide conformations in a (GT)7-SWCN hybrid. We calculate the free energy landscape and find minima corresponding to six distinct conformations, with a nonhelical loop structure as the global minimum. The hybrid contains significant structural disorder, with desorbed bases as an important structural feature. These results expand our understanding of DNA-CN and indicate the relevance of REMD for explorations of the physical properties of organic−inorganic multifunctional nanomaterials. [ABSTRACT FROM AUTHOR]

Self-assembly at a liquid−liquid interface is a powerful experimental route to novel nanomaterials. We report herein a computational study of peptide nanotube formation at an oil−water interface. We probe interfacial self-assembly and nanotube formation of the cyclic octapeptide, cyclo[(- l-Trp- d-Leu-) 4] as an illustrative example. Individual peptide rings are rapidly adsorbed at the liquid−liquid interface where they self-assemble. Monomeric and dimeric peptide rings lie with their molecular planes mostly parallel to the interface. Longer oligomeric nanotubes are increasingly tilted at the interface and grow by an Oswald ripening mechanism to eventually align their tube axis parallel to the interface. The present results on nanotube assembly suggest that computation will be a useful complement to experiment in understanding the nature of self-assembly of nanomaterials at liquid−liquid interfaces. [ABSTRACT FROM AUTHOR]

Dinuclear azole-bridged Pt compounds bind to DNA helices, forming intrastrand crosslinks between adjacent guanines in a similar way to cisplatin. Their cytotoxic profile is, however, different from that of first and second generation Pt drugs in that they lack cross resistance in cisplatin-resistant cell lines. In contrast to cisplatin, which induces a large kink in DNA duplex, structural NMR studies and molecular dynamics simulations have shown that azole-bridged diplatinum compounds induce only small structural changes in double-stranded DNA. These structural differences have been invoked to explain the different cytotoxic profile of these compounds. Here, we show that in addition to the small structural changes in DNA, dinuclear Pt compounds also affect DNA minor groove flexibility in a different way than cisplatin. Free-energy calculations on azole-bridged diplatinum DNA adducts reveal that opening of the minor groove requires a higher free-energy cost (G ∼ 7−15 kcal/mol) than in the corresponding cisplatin-DNA adduct (G ∼ 0 kcal/mol). This could prevent minor groove binding proteins from binding to diplatinum-DNA adducts thus leading to a different cellular response than cisplatin and possibly decreasing the activity of excision repair enzymes. Although the development of drug resistance is a highly complex mechanism, our findings provide an additional rationale for the improved cytotoxic activity of these compounds in cell lines resistant to cisplatin. [ABSTRACT FROM AUTHOR]

The self-assembly of cyclic d,l--peptides into hollow nanotubes is a crucial mechanistic step in their application as antibacterial and drug-delivery agents. To understand this process, molecular dynamics (MD) simulations were performed on dimers of cyclic peptides formed from cyclo (-l-Trp-d-N-MeLeu-)4-2and cyclo (-l-Trp-d-Leu-)4-2subunits in nonpolar (nonane) and polar (water) solvent. The dimers were observed to be stable only in nonpolar solvent over the full 10 ns length of the MD trajectory. The behavior of the dimers in different solvents is rationalized in terms of the intersubunit hydrogen bonding, hydrogen bonding with the solvent, and planarity of the rings. It is shown that the and dihedral angles of a single uncapped ring in nonane lie in the -sheet region of the Ramachandran plot, and the ring stays in a flat conformation. Steered MD (SMD) simulations based on Jarzynski's equality were performed to obtain the potential of mean force as a function of the distance between the two rings of the capped dimer in nonane. It is also shown that a single peptide subunit prefers to reside close to the nonane/water interface rather than in bulk solvent because of the amphiphilic character of the peptide ring. The present MD results build the foundation for using MD simulations to study the mechanism of the formation of cyclic peptide nanotubes in lipid bilayers. [ABSTRACT FROM AUTHOR]

Accurate calculation of pKa values and free energies for acid/base reactions in the condensed phase has been a long-standing goal of theoretical chemistry. We present a novel application of the Car−Parrinello molecular dynamics method to the problem of relative pKa determination. As a particular example, we focus on the second stage in the dissociation of histidine, a process that holds special importance for biology. Using constrained molecular dynamics, we have analyzed the structural, electronic, and dynamical transformations taking place along a preselected, intuitive reaction coordinate. By integrating the potentials of mean force for the deprotonation of histidine and for a reference reaction, autodissociation of water, we obtain a pKa value of 6.8, which appears to be in good agreement with the experimental estimate of 6.1. Detailed analysis was undertaken to determine the value of the constraint, which transformed the N*−H* from a covalent to a hydrogen bond. This helped to identify a number of properties that could be successfully used in monitoring the dissociation process. Additional analysis in terms of electron localization functions provided valuable insight into the nature of the deprotonation reaction. [ABSTRACT FROM AUTHOR]