Electroactive Carbazole-Based Polycyclic Aromatic Hydrocarbons: Synthesis, Photophysical Properties, and Computational Studies.

Herein, we explored the oxidative coupling reactions of carbazole-based polycyclic aromatic hydrocarbons using traditional Scholl reactions and electrochemical oxidation. Our findings indicate that the oxidation predominantly occurs at the carbazole functional group. The underlying reaction mechanisms were also clarified through theoretical investigations, highlighting that the primary oxidation pathway involves the 3,6-positions of the carbazole moiety, which is attributable to its high electron density.

Steric Effects on the Photovoltaic Performance of Panchromatic Ruthenium Sensitizers for Dye-Sensitized Solar Cells.

Three new heteroleptic Ru complexes, CYC-B22, CYC-B23C, and CYC-B23T, were prepared as sensitizers for coadsorbent-free, panchromatic, and efficient dye-sensitized solar cells. They are simultaneously functionalized with highly conjugated anchoring and ancillary ligands to explore the electronic and steric effects on their photovoltaic characteristics. The coadsorbent-free device based on CYC-B22 achieved the best power conversion efficiency (PCE) of 8.63% and a panchromatic response extending to 850 nm. The two stereoisomers, CYC-B23C and CYC-B23T coordinated with an unsymmetrical anchoring ligand, display similar absorption properties and the same driving forces for electron injection as well as dye regeneration. Nevertheless, the devices show not only the remarkably distinct PCE (6.64% vs 8.38%) but also discernible stability. The molecular simulation for the two stereoisomers adsorbed on TiO2 clarifies the distinguishable distances (16.9 Å vs 19.0 Å) between the sulfur atoms in the NCS ligands and the surface of the TiO2, dominating the charge recombination dynamics and iodine binding and therefore the PCE and stability of the devices. This study on the steric effects caused by the highly conjugated and unsymmetrical anchoring ligand on the adsorption geometry and photovoltaic performance of the dyes paves a new way for advancing the molecular design of polypyridyl metal complex sensitizers.

Accelerating Antimicrobial Peptide Discovery for WHO Priority Pathogens through Predictive and Interpretable Machine Learning Models.

The escalating menace of multidrug-resistant (MDR) pathogens necessitates a paradigm shift from conventional antibiotics to innovative alternatives. Antimicrobial peptides (AMPs) emerge as a compelling contender in this arena. Employing in silico methodologies, we can usher in a new era of AMP discovery, streamlining the identification process from vast candidate sequences, thereby optimizing laboratory screening expenditures. Here, we unveil cutting-edge machine learning (ML) models that are both predictive and interpretable, tailored for the identification of potent AMPs targeting World Health Organization's (WHO) high-priority pathogens. Furthermore, we have developed ML models that consider the hemolysis of human erythrocytes, emphasizing their therapeutic potential. Anchored in the nuanced physical-chemical attributes gleaned from the three-dimensional (3D) helical conformations of AMPs, our optimized models have demonstrated commendable performance-boasting an accuracy exceeding 75% when evaluated against both low-sequence-identified peptides and recently unveiled AMPs. As a testament to their efficacy, we deployed these models to prioritize peptide sequences stemming from PEM-2 and subsequently probed the bioactivity of our algorithm-predicted peptides vis-à-vis WHO's priority pathogens. Intriguingly, several of these new AMPs outperformed the native PEM-2 in their antimicrobial prowess, thereby underscoring the robustness of our modeling approach. To elucidate ML model outcomes, we probe via Shapley Additive exPlanations (SHAP) values, uncovering intricate mechanisms guiding diverse actions against bacteria. Our state-of-the-art predictive models expedite the design of new AMPs, offering a robust countermeasure to antibiotic resistance. Our prediction tool is available to the public at https://ai-meta.chem.ncu.edu.tw/amp-meta.

Enhancing Near-Infrared Absorption in Terpyridyl Ru/Os Complexes with Ancillary Ligands to Activate Spin-Forbidden Transitions in Dye-Sensitized Solar Cells: A TDDFT Investigation.

Dye sensitizers with wideband absorption covering the near-IR region have long been of interest because they potentially harvest a wide range of solar energies essential to promote photocurrent power conversion efficiencies. In this study, we used time-dependent density functional theory with spin-orbit (SO) interactions to theoretically explore the long-wavelength absorptions and spin-forbidden triplet transitions activated by SO interactions for terpyridyl ruthenium/osmium complex dyes. These dyes feature a Ru(II) sensitizer coordinated with a phosphine ligand and are exemplified by DX1, denoted as [trans-dichloro-(phenyldimethoxyphosphine)(2,2';6',2″-terpyridyl-4,4',4″-tricarboxylic)Ru]. We found that ancillary ligands significantly affected the longest wavelength spin-allowed absorption, with NCS- ligands yielding longer wavelength S1 transitions than halides. High atomic number halide ligands caused blue shifts in the S1 transition. Os complexes consistently exhibited longer wavelength S1 transitions than Ru complexes with identical ligands. In Ru/Os complexes, ancillary ligands with higher atomic numbers have a more pronounced effect in activating spin-forbidden triplet transitions through spin-orbit coupling (SOC) than those with lower atomic numbers. The absorption wavelength of the SOC-activated transition primarily depended on the energy of lower lying triplet states. Some complexes exhibited T1 states activated by SOC, leading to longer wavelength absorption than that of SOC-activated T2 states. Our study revealed the significance of ancillary ligands and SOC interactions in Ru/Os complexes, offering insights for optimizing materials with enhanced long-wavelength absorption properties, particularly in the near-IR range, for photovoltaic and optoelectronic applications.

Robust enhancement of motor sequence learning with 4 mA transcranial electric stimulation.

BACKGROUND AND OBJECTIVES: Motor learning experiments with transcranial direct current stimulation (tDCS) at 2 mA have produced mixed results. We hypothesize that tDCS boosts motor learning provided sufficiently high field intensity on the motor cortex. METHODS: In a single-blinded design, 108 healthy participants received either anodal (N = 36) or cathodal (N = 36) tDCS at 4 mA total, or no stimulation (N = 36) while they practiced a 12-min sequence learning task. Anodal stimulation was delivered across four electrode pairs (1 mA each), with anodes above the right parietal lobe and cathodes above the right frontal lobe. Cathodal stimulation, with reversed polarities, served as an active control for sensation, while the no-stimulation condition established baseline performance. fMRI-localized targets on the primary motor cortex in 10 subjects were used in current flow models to optimize electrode placement for maximal field intensity. A single electrode montage was then selected for all participants. RESULTS: We found a significant difference in performance with anodal vs. cathodal stimulation (Cohen's d = 0.71) and vs. no stimulation (d = 0.56). This effect persisted for at least 1 h, and subsequent learning for a new sequence and the opposite hand also improved. Sensation ratings were comparable in the active groups and did not exceed moderate levels. Current flow models suggest the new electrode montage can achieve stronger motor cortex polarization than alternative montages. CONCLUSION: The present paradigm shows a medium to large effect size and is well-tolerated. It may serve as a go-to experiment for future studies on motor learning and tDCS.

Double Proton Transfer during a Novel Tertiary α-Ketol Rearrangement in Ketol-Acid Reductoisomerase: A Water-Mediated, Metal-Catalyzed, Base-Induced Mechanism.

(KARI) catalyzes the conversion of (S)-2-acetolactate or (S)-2-aceto-2-hydroxybutyrate to 2,3-dihydroxy-3-alkylbutyrate, the second step in the biosynthesis of branched chain amino acids (BCAAs). Because the BCAA biosynthetic pathway is present in bacteria, plants, and fungi, but absent in animals, it is an excellent target for the development of new-generation antibiotics and herbicides. Nevertheless, the mechanism of the KARI-catalyzed reaction has not yet been fully solved. In this study, we used iterative molecular dynamics (MD) flexible fitting-Rosetta techniques to optimize the three-dimensional solution structure of archaea KARI from Sulfolobus solfataricus (Sso-KARI) determined from cryo-electron microscopy. On the basis of the structure of the Sso-KARI/2Mg2+/NADH/(S)-2-acetolactate complex, we deciphered the catalytic mechanism of the KARI-mediated reaction through hybrid quantum mechanics/molecular mechanics MD simulations in conjunction with umbrella sampling. With an activation energy of only 6.06 kcal/mol, a water-mediated, metal-catalyzed, base-induced (WMMCBI) mechanism was preferred for deprotonation of the tertiary OH group of (S)-2-acetolactate in Sso-KARI. The WMMCBI mechanism for double proton transfer occurred within a proton wire route with two steps involving the formation of hydroxide: (i) Glu233 served as a general base to deprotonate the Mg2+-bound water, forming a hydroxide-coordinated Mg2+ ion; (ii) this hydroxide ion acted as a strong base that rapidly deprotonated the ternary OH group of the substrate. In contrast, the direct deprotonation of the substrate by Glu233 was kinetically unfavorable. This mechanism suggests a novel approach for designing catalysts for deprotonation and provides clues for the development of new-generation antibiotics and herbicides.

Cutaneous sensation of electrical stimulation waveforms.

BACKGROUND: Skin sensation is the primary factor limiting the intensity of transcranial electrical stimulation (tES). It is well established that different waveforms generate different sensations, yet transcranial stimulation has been limited to a relatively small number of prototypical waveforms. OBJECTIVE: We explore whether alternative stimulation waveforms could substantially reduce skin sensation and thus allow for stronger intensities in tES. METHODS: We systematically tested a range of waveforms in a series of 6 exploratory experiments stimulating human adults on the forearm and in one instance on the head. Subjects were asked to rate skin sensation level on a numerical scale from "none" to "extreme". RESULTS: High frequency (>1 kHz) monophasic square wave stimulation was found to decrease in sensation with increasing duty cycle, baseline, and frequency, but the sensation was never lower than for constant current stimulation. For the purpose of injecting a net direct current (DC), a constant current is optimal. For stimulation with alternating current (AC), sensation decreased with increasing frequency, consistent with previous reports. Amplitude modulation did not reduce sensation below stimulation with constant AC amplitude, and biphasic square waveforms produced higher sensation levels than biphasic sinusoidal waveforms. Furthermore, for DC stimulation, sensation levels on the arm were similar to those reported on the head. CONCLUSION: Our comparisons of various waveforms for monophasic and biphasic stimulation indicate that conventional DC and AC waveforms may provide the lowest skin sensations levels for transcutaneous electrical stimulation. These results are likely generalizable to tES applications.

Ligand Exchange in the Synthesis of Metal-Organic Frameworks Occurs Through Acid-Catalyzed Associative Substitution.

The syntheses of metal-organic frameworks (MOFs) can be improved through modulated synthesis, synthesis employing precursors, and postsynthetic exchange (PSE) modifications, all of which share ligand exchange as a common and crucial reaction. To date, however, the mechanism of ligand exchange and the underlying principles governing it have remained elusive. Herein, we report energy landscapes for the ligand exchange processes of 1,4-benzenedicarboxylic acid and 2,3,5,6-tetrafluoro-1,4-benzenedicarboxylic acid with Zr6O4(OH)4(OMc)12 (OMc = methacrylate), as calculated using density functional theory (DFT). The rate-limiting step of ligand exchange follows an associative-substitution mechanism catalyzed by protons, consistent with previous kinetic data. Our calculations suggest that the acid catalysis is dependent on the relative basicities of the incoming and outgoing ligands coordinated in the complex, allowing molecular-level rationalization of many seminal MOF syntheses that had previously been interpreted macroscopically. Our results provide new insights for MOF synthesis and new clues for the rational de novo synthesis of MOFs.

Unusually Long-Wavelength Emissions of Cyclopropanes: New Insight into C-C Bond Homolysis.

Bond homolysis (BHo) is a fundamental concept in chemical-bonding phenomena. To date, research studies on the BHo concept have provided crucial information for understanding the nature of chemical bonding and reactions. Two potential-energy minima, a σ-bonding isomer and a singlet-diradical isomer, have been known to exist in carbon-carbon BHo. Herein, a third isomer, that is, a puckered singlet diradical exhibiting unstructured long-wavelength fluorescence beyond 460 nm, was first observed in the excited states of 1,4-diarylbicyclo[2.1.0]pentane derivatives. The careful selection of appropriate substituents in the bicyclic structures enabled direct spectral detection. State-of-the-art ab initio quantum chemical calculations quantitatively reproduced the experimental observations. This new finding provides new insight into carbon-carbon bond-breaking and -forming processes.

Effects of Internal Electron-Withdrawing Moieties in D-A-π-A Organic Sensitizers on Photophysical Properties for DSSCs: A Computational Study.

D-A-π-A dyes differ from the traditional D-π-A framework having several merits in dye-sensitized solar cell (DSSC) applications. With regard to D-π-A dyes, D-A-π-A dyes red-shift absorption spectra and show particular photostability. Nevertheless, the effects of internal acceptor on the charge transfer (CT) probability are unclear. We employed density functional theory (DFT), time-dependent DFT (TD-DFT), and TD-DFT molecular dynamics (MD) simulations to investigate the effects of internal acceptor on the photophysical properties of D-A-π-A dyes on DSSCs. Our calculations show the absorption bands of D-A-π-A dyes with strong electron-withdrawing internal acceptors exhibiting significant characteristics of dual CT; the excited electron density is transferred to the internal and terminal acceptors simultaneously. Particularly, the internal acceptor traps a significant amount of electron density upon photoexcitation. The TD-DFT MD simulations at 300 K show that only a small amount of excited electron density is pushing and pulling between the internal acceptor and terminal acceptor moieties; the thermal energy is not high enough to drive the electron density from the internal acceptor to the terminal acceptor. Our study reveals the nature of CT bands of D-A-π-A dyes providing a theoretical basis for further rational engineering.

The Arginine Pairs and C-Termini of the Sso7c4 from Sulfolobus solfataricus Participate in Binding and Bending DNA.

The Sso7c4 from Sulfolobus solfataricus forms a dimer, which is believed to function as a chromosomal protein involved in genomic DNA compaction and gene regulation. Here, we present the crystal structure of wild-type Sso7c4 at a high resolution of 1.63 Å, showing that the two basic C-termini are disordered. Based on the fluorescence polarization (FP) binding assay, two arginine pairs, R11/R22' and R11'/R22, on the top surface participate in binding DNA. As shown in electron microscopy (EM) images, wild-type Sso7c4 compacts DNA through bridging and bending interactions, whereas the binding of C-terminally truncated proteins rigidifies and opens DNA molecules, and no compaction of the DNA occurs. Moreover, the FP, EM and fluorescence resonance energy transfer (FRET) data indicated that the two basic and flexible C-terminal arms of the Sso7c4 dimer play a crucial role in binding and bending DNA. Sso7c4 has been classified as a repressor-like protein because of its similarity to Escherichia coli Ecrep 6.8 and Ecrep 7.3 as well as Agrobacterium tumefaciens ACCR in amino acid sequence. Based on these data, we proposed a model of the Sso7c4-DNA complex using a curved DNA molecule in the catabolite activator protein-DNA complex. The DNA end-to-end distance measured with FRET upon wild-type Sso7c4 binding is almost equal to the distance measured in the model, which supports the fidelity of the proposed model. The FRET data also confirm the EM observation showing that the binding of wild-type Sso7c4 reduces the DNA length while the C-terminal truncation does not. A functional role for Sso7c4 in the organization of chromosomal DNA and/or the regulation of gene expression through bridging and bending interactions is suggested.

Long-Range Olefin Isomerization Catalyzed by Palladium(0) Nanoparticles.

Long-range olefin isomerization of 2-alkenylbenzoic acid derivatives going through two to five sp3-carbon atoms to give (E)-alkenes was achieved with palladium(0) nanoparticles. The substrate scope of this reaction includes carboxylic acid, ester, and primary to tertiary amides and tolerates various substituents on the benzene ring. This isomerization reaction was catalyzed by recyclable Pd(0) nanoparticles, prepared in situ from PdCl2 and characterized by X-ray powder diffraction and scanning electron microscopy analyses. 1H NMR studies and kinetic modeling supported a stepwise process. This new process was applied to synthesize a natural dihydroisocoumarin with good efficiency.

First-Principle Characterization of the Adsorption Configurations of Cyanoacrylic Dyes on TiO2 Film for Dye-Sensitized Solar Cells.

The loading of sensitizers on a semiconductor is crucial for determining the light-harvesting efficiency of dye-sensitized solar cells (DSSCs). The interfacial properties of dyes adsorbed on a TiO2 film, such as adsorption configurations and adsorption energy, can influence the total amount of dye sensitizers that loads and the stability of a DSSC device. Therefore, it is important to characterize the adsorption properties of sensitizers on TiO2 films atomically and electronically to ensure rational structure-based dye design for high-performance DSSCs. Due to the complex properties of interfacial dyes, previous works on the identification of adsorption configurations of dyes on TiO2 have sometimes been controversial, in particular, the essential IR band assignments. In this study, we employed density functional theory to investigate the adsorption energies, geometries, and vibrational frequencies of various adsorption configurations of 2-cyano-3-(thiophen-2-yl)acrylic acid adsorbed on TiO2. We performed a comparative assignment of the calculated vibrational peaks of tridentate and bidentate configurations to the experimental FT-IR spectra simultaneously. Our work backs up the coexistence of tridentate and bidentate bridging configurations, first proposed by Meng and co-workers. Moreover, our comparative IR mode assignments provide clues for further studies of the interfacial properties of dyes adsorbed on TiO2. Study of the transformation mechanisms between tridentate and bidentate modes suggests that the bidentate bridging configuration is a kinetically trapped adsorption mode and the tridentate configuration is thermodynamically the most stable one. Finally, we investigated the photophysical properties of a D-π-A dye in tridentate and bidentate adsorption configurations.

Geometrical effects of phospholipid olefinic bonds on the structure and dynamics of membranes: A molecular dynamics study.

The trans isomers of fatty acids are found in human adipose tissue. These isomers have been linked with deleterious health effects (e.g., coronary artery disease). In this study, we performed molecular dynamics simulations to investigate the structures and dynamic properties of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) and 1-palmitoyl-2-elaidoyl sn-glycero-3-phosphatidylcholine (PEPC) lipid bilayers. The geometry of the olefinic bond and membrane packing effects significantly influenced the conformations and dynamics of the two C-C single bonds adjacent to the olefinic bond. For the PEPC lipid, the two C-C single bonds adjacent to the olefinic bond adopted mainly nonplanar skew-trans and planar cis-trans motifs; although the cis conformation featured relatively strong steric repulsion, it was stabilized through membrane packing because its planar structure is more suitable for membrane packing. Moreover, membrane packing effects stabilized the planar transition state for conformational conversion to a greater extent than they did with the nonplanar transition state, thereby affecting the dynamics of conformational conversion. The rotational motions of the first neighboring C-C single bonds were much faster than those of typical saturated C-C single bonds; in contrast, the rotational motions of the second neighboring C-C single bonds were significantly slower than those of typical saturated torsion angles. The packing of PEPC lipids is superior to that of POPC lipids, leading to a smaller area per lipid, a higher order parameter and a smaller diffusion coefficient. The distinct properties of POPC and PEPC lipids result in PEPC lipids forming microdomains within a POPC matrix.

Location and conformation of amyloid ß(25-35) peptide and its sequence-shuffled peptides within membranes: implications for aggregation and toxicity in PC12 cells.

Extracellular deposits of amyloid ß (Aß) aggregates in the brain is the hallmark of Alzheimer's disease. We present the configurations (location and conformation) and the interfacial folding and membrane insertion mechanisms of Aß fragments, wild-type Aß(25-35), Aß(35-25), and a sequence-shuffled peptide [Aß(25-35)-shuffled] from Aß(25-35) within membranes by replica-exchange molecular dynamics simulations. Although these peptides have the same amino acid composition, simulations show they have distinct locations and conformations within membranes. Moreover, our in vitro experiments show that these peptides have distinct neurotoxicities. We rationalize the distinct neurotoxicities of these peptides in terms of their simulated locations and conformations in membranes. This work provides another view that complements the general hydrophobicity-toxicity views, to better explain the neurotoxicity of Aß peptides.

Multi-step formation of a hemifusion diaphragm for vesicle fusion revealed by all-atom molecular dynamics simulations.

Membrane fusion is essential for intracellular trafficking and virus infection, but the molecular mechanisms underlying the fusion process remain poorly understood. In this study, we employed all-atom molecular dynamics simulations to investigate the membrane fusion mechanism using vesicle models which were pre-bound by inter-vesicle Ca(2+)-lipid clusters to approximate Ca(2+)-catalyzed fusion. Our results show that the formation of the hemifusion diaphragm for vesicle fusion is a multi-step event. This result contrasts with the assumptions made in most continuum models. The neighboring hemifused states are separated by an energy barrier on the energy landscape. The hemifusion diaphragm is much thinner than the planar lipid bilayers. The thinning of the hemifusion diaphragm during its formation results in the opening of a fusion pore for vesicle fusion. This work provides new insights into the formation of the hemifusion diaphragm and thus increases understanding of the molecular mechanism of membrane fusion. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

Molecular mechanism of Ca(2+)-catalyzed fusion of phospholipid micelles.

Although membrane fusion plays key roles in intracellular trafficking, neurotransmitter release, and viral infection, its underlying molecular mechanism and its energy landscape are not well understood. In this study, we employed all-atom molecular dynamics simulations to investigate the fusion mechanism, catalyzed by Ca(2+) ions, of two highly hydrated 1-palmitoyl-2-oleoyl-sn-3-phosphoethanolamine (POPE) micelles. This simulation system mimics the small contact zone between two large vesicles at which the fusion is initiated. Our simulations revealed that Ca(2+) ions are capable of catalyzing the fusion of POPE micelles; in contrast, we did not observe close contact of the two micelles in the presence of only Na(+) or Mg(2+) ions. Determining the free energy landscape of fusion allowed us to characterize the underlying molecular mechanism. The Ca(2+) ions play a key role in catalyzing the micelle fusion in three aspects: creating a more-hydrophobic surface on the micelles, binding two micelles together, and enhancing the formation of the pre-stalk state. In contrast, Na(+) or Mg(2+) ions have relatively limited effects. Effective fusion proceeds through sequential formation of pre-stalk, stalk, hemifused-like, and fused states. The pre-stalk state is the state featuring lipid tails exposed to the inter-micellar space; its formation is the rate-limiting step. The stalk state is the state where a localized hydrophobic core is formed connecting two micelles; its formation occurs in conjunction with water expulsion from the inter-micellar space. This study provides insight into the molecular mechanism of fusion from the points of view of energetics, structure, and dynamics.

Synthesis of the decalin core of codinaeopsin via an intramolecular Diels-Alder reaction.

We describe the synthesis of the decalin core of codinaeopsin (1), a tryptophan-polyketide hybrid natural product with promising antimalarial activity (IC50 4.7 µM, against Plasmodium falciparum), via an intramolecular Diels-Alder (IMDA) reaction. A convergent synthesis was developed to prepare the precursors for the IMDA reaction in 10 steps. The exo cycloadducts were derived from thermal, IMDA reactions of the substrates containing a Weinreb amide or ester conjugated dienophile, and the endo adducts were from Lewis acid promoted reactions of the substrates with a formyl group. Both exo and endo products of the IMDA were exclusively isolated and characterized by NMR spectroscopy. One endo cycloadduct was further confirmed with X-ray crystallography. Theoretical calculations reveal the influence of the substituents of the decalin core on the IMDA process.

A molecular dynamics study of the structural and dynamical properties of putative arsenic substituted lipid bilayers.

Cell membranes are composed mainly of phospholipids which are in turn, composed of five major chemical elements: carbon, hydrogen, nitrogen, oxygen, and phosphorus. Recent studies have suggested the possibility of sustaining life if the phosphorus is substituted by arsenic. Although this issue is still controversial, it is of interest to investigate the properties of arsenated-lipid bilayers to evaluate this possibility. In this study, we simulated arsenated-lipid, 1-palmitoyl-2-oleoyl-sn-glycero-3-arsenocholine (POAC), lipid bilayers using all-atom molecular dynamics to understand basic structural and dynamical properties, in particular, the differences from analogous 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, (POPC) lipid bilayers. Our simulations showed that POAC lipid bilayers have distinct structural and dynamical properties from those of native POPC lipid bilayers. Relative to POPC lipid bilayers, POAC lipid bilayers have a more compact structure with smaller lateral areas and greater order. The compact structure of POAC lipid bilayers is due to the fact that more inter-lipid salt bridges are formed with arsenate-choline compared to the phosphate-choline of POPC lipid bilayers. These inter-lipid salt bridges bind POAC lipids together and also slow down the head group rotation and lateral diffusion of POAC lipids. Thus, it would be anticipated that POAC and POPC lipid bilayers would have different biological implications.

Molecular dynamics simulation of cation-phospholipid clustering in phospholipid bilayers: possible role in stalk formation during membrane fusion.

In this study, we performed all-atom long-timescale molecular dynamics simulations of phospholipid bilayers incorporating three different proportions of negatively charged lipids in the presence of K(+), Mg(2+), and Ca(2+) ions to systemically determine how membrane properties are affected by cations and lipid compositions. Our simulations revealed that the binding affinity of Ca(2+) ions with lipids is significantly stronger than that of K(+) and Mg(2+) ions, regardless of the composition of the lipid bilayer. The binding of Ca(2+) ions to the lipids resulted in bilayers having smaller lateral areas, greater thicknesses, greater order, and slower rotation of their lipid head groups, relative to those of corresponding K(+)- and Mg(2+)-containing systems. The Ca(2+) ions bind preferentially to the phosphate groups of the lipids. The complexes formed between the cations and the lipids further assembled to form various multiple-cation-centered clusters in the presence of anionic lipids and at higher ionic strength-most notably for Ca(2+). The formation of cation-lipid complexes and clusters dehydrated and neutralized the anionic lipids, creating a more-hydrophobic environment suitable for membrane aggregation. We propose that the formation of Ca(2+)-phospholipid clusters across apposed lipid bilayers can work as a "cation glue" to adhere apposed membranes together, providing an adequate configuration for stalk formation during membrane fusion.