Atomistic Molecular Dynamics Simulations Research Articles

Sulfoglycodendron Antivirals with Scalable Architectures and Activities.

Many viruses initiate their cell-entry by binding their multi-protein receptors to human heparan sulfate proteoglycans (HSPG) and other molecular components present on cellular membranes. These viral interactions could be blocked and the whole viruses could be eliminated by suitable HSPG-mimetics providing multivalent binding to viral protein receptors. Here, large sulfoglycodendron HSPG-mimetics of different topologies, structures, and sizes were designed to this purpose. Atomistic molecular dynamics simulations were used to examine the ability of these broad-spectrum antivirals to block multi-protein HSPG-receptors in HIV, SARS-CoV-2, HPV, and dengue viruses. To characterize the inhibitory potential of these mimetics, their binding to individual and multiple protein receptors was examined. In particular, vectorial distributions of binding energies between the mimetics and viral protein receptors were introduced and calculated along the simulated trajectories. Space-dependent residual analysis of the mimetic-receptor binding was also performed. This analysis revealed detail nature of binding between these antivirals and viral protein receptors, and provided evidence that large inhibitors with multivalent binding might act like a molecular glue initiating the self-assembly of protein receptors in enveloped viruses.

Exploring the adsorption of 4,4’-[oxalylbis(imino)]bis(2-hydroxybenzoic acid) layer at steel/biogasoline interface by the combined electrical-optical-simulation approach

Reactions at the steel/biogasoline interface trigger the adsorption of 4,4’-[Oxalylbis(imino)]bis(2-hydroxybenzoic Acid) (ODA) layer on the steel surface, thereby activating a mechanism that inhibited the early reactions. Exploring the conditionally deposited ODA layer requires a combined approach, including electrical, optical, and simulation techniques to track the film development and coating characteristics over time, and with the assistance of atomic force microscopy, quantum chemistry (DFT), and molecular dynamics (MD) simulations to reveal the adsorption mechanism of the ODA layer at steel/biogasoline interface. The four experimental ODA concentrations were conducted, related to the simulated un-coverage, undersaturated-, saturated-, and oversaturated-coverage model of the adsorbate on the adsorbent. The EC-RS data examines surface compositions and their distribution, coating/solution interface, and coating/substrate adhesion by, respectively, Raman spectroscopy (RS), electrochemical impedance spectroscopy (EIS), and current density—potential (I-V) scan. Namely, RS pointed out that an organic layer was established when ODA was added to the simulated biogasoline. EIS results revealed insulator behaviors of the ODA layer at the solid–liquid interface, limiting the charge transfer between the steel substrate and the biogasoline. I-V results showed an increase in surface current density and a decrease in surface polarization resistance of the coating with the rise in ODA concentration. The AFM morphology profile verified the degradation of the sample’s surface when exposed to biogasoline and the minimization of surface damage by ODA addition through adsorption. The simulation findings revealed that the adsorption of ODA on steel preferred physisorption, reaching the most stable state at a specified temperature and ODA concentration. The adsorption mechanism follows the Generalized Langmuir isotherm. The adsorbate (ODA molecules) can produce a transition phase with the steel substrate surface, which modifies the surface thermodynamic characteristics. The combined electro-optical-simulation technique can be applied to investigate various surface phenomena (reactions, catalyzes, adsorption). It especially helps to understand the protective mechanism of inhibitors in different media.

Molecular interaction of a protease inhibitor, leupeptin, with human serum albumin: Insights from calorimetry, spectroscopy, microscopy, and computational approaches

Leupeptin (LPN) possesses anti-inflammatory and inhibitory effects on periodontitis and gingivitis, and it also inhibits human coronavirus and SARS-CoV-2 in cells. The characterisation of its interaction with human serum albumin (HSA), the key transport protein in the blood circulation of the human body, contributes essential information to the drug's pharmacokinetic properties. Various techniques, such as isothermal titration calorimetry (ITC), circular dichroism (CD) spectroscopy, atomic force microscopy (AFM), molecular docking, and molecular dynamics simulation (MDS), were employed to characterise the LPN-HSA interaction. The ITC result revealed a moderate binding affinity in the LPN-HSA interaction with a binding constant (Ka) value of 4.27 ± 0.27 × 106 M−1. The thermodynamic analysis indicated that LPN binding to HSA was spontaneous, resulting from a negative Gibbs free energy change (∆G° = − 37.91 ± 0.04 kJ mol−1) and involving an exothermic reaction due to a combination of a negative enthalpy change (∆H° = − 11.4 ± 0.9 kJ mol−1) and a positive entropy change (∆S° = 88.82 ± 3.4 J mol−1K−1). The HSA secondary structure remained unaltered upon the addition of LPN, as evident from the far-UV CD results. AFM results showed HSA morphological changes induced by LPN binding due to the occurrence of aggregates in the LPN-HSA complex. Molecular docking results predicted that LPN preferably binds to site III of HSA, involving hydrogen bonds, electrostatic, van der Waals forces, and hydrophobic forces. The MDS demonstrated a slight deviation and fluctuation, which supported the overall stability of the LPN-HSA system. Thus, these findings provide additional information on the pharmacokinetics of this drug and contribute to designing new drugs for clinical use, particularly those related to inflammatory diseases.

Dissipative Particle Dynamics Simulation of Protein Folding in Explicit and Implicit Solvents: Coarse-Grained Model for Atomic Resolution.

Advancements have been made to dissipative particle dynamics (DPD), a robust coarse-grained (CG) simulation method, to study the folded structures of four miniproteins (1L2Y, 1WN8, 1YRF, and 2I9M) in explicit and implicit solvents. In this endeavor, we aim to establish model parametrization and enhance computational efficiency. Unlike traditional CG models that use empirical force parameters, ex-force parameters (r0(ex), , δd, δp) of DPD particles constructed for specific research purposes can be obtained from atomistic molecular dynamics simulations. On the other hand, im-force parameters (r0(im), c, σ) can be derived from ex-DPD simulations, according to the underlying thermodynamic theory. Based on a mapping scheme proposed for the modeling of amino acids, all-atom proteins can be converted into a CG model. Both ex-/im-DPDs are then carried out to investigate the folding pathways of the four mini-proteins. Structural analysis of the RMSDs shows that the im-simulated proteins have greater structural similarity to native proteins than the ex-simulated ones. The constructed CG models achieve a resolution of Angstrom (Å), a level normally associated with atomic models. Additionally, speed tests reveal that im-DPD accelerates the simulation process and significantly improves simulation efficiency.

Colloidal Nafion in Liquid Media: Insight from SANS Analysis and Molecular Dynamics Simulations

Colloidal Nafion™ morphology in liquid media plays a critical role in determining the electrode performance of fuel cells and electrolyzers. In this presentation, we demonstrate that commonly reported, cylindrical morphologies of Nafion in liquid media are not ubiquitous among Nafion dispersions and assuming such may provide inaccurate information.1 Here we compare colloidal Nafion™ morphology in N-methyl-pyrrolidone (NMP) and water using small angle neutron scattering (SANS) and all atomistic molecular dynamics simulations (MD).2 Our SANS analyses using model-dependent and model-independent techniques combined with MD simulations demonstrated highly gel-like particles best describe Nafion particles in NMP, which is in stark contrast to the commonly assumed cylindrical morphology. In high dielectric constant dispersants such as water, the cylindrical morphology is a feasible choice to describe the scattering data, however, the particle radius is much lower than previous report (R = 10 Å). MD simulations support the SANS analysis and show that the sulfonic acid groups are fully dissociated and strongly solvated on the outer wall of the particle suggesting that the structure is driven by hydrophobic interactions.References Aldebert, B. Dreyfus, G. Gebel, N. Nakamura, M. Pineri, F. Volino, Macromolecules, 19, 2651-2653 (1986). Jeffrey M. Klein, Cynthia Welch, Sathish Ponnurangam, Atefeh Tarokh, Kunal Karan, Marilyn E. Hawley, Anna Sokolova, Sung-Dae Yim, Rex P. Hjelm, Yu Seung Kim, ACS Macro Letters, 12, 1648-1653 (2023).

Molecular Density Fluctuations Control Solubility and Diffusion for Confined Aqueous Hydrogen.

Hydrogen's contribution to a sustainable energy transformation requires intermittent storage technologies, e.g., underground hydrogen storage (UHS). Toward designing UHS sites, atomistic molecular dynamics (MD) simulations are used here to quantify thermodynamic and transport properties for confined aqueous H2. Slit-shaped pores of width 10 and 20 Å are carved out of kaolinite. Within these pores, water yields pronounced hydration layers. Molecular H2 distributes along these hydration layers, yielding solubilities up to ∼25 times those in the bulk. Hydrogen accumulates near the siloxane surface, where water density fluctuates significantly. On the contrary, a dense hydration layer forms on the gibbsite surface, which is, for the most part, depleted of H2. Although confinement reduces water mobility, the diffusion of aqueous H2 increases as the kaolinite pore width decreases, also a consequence of water density fluctuations. These results relate to H2 permeability in underground hydrogen storage sites.

Influence of chirality and sequence in lysine-rich lipopeptide biosurfactants and micellar model colloid systems

Lipopeptides can self-assemble into diverse nanostructures which can be programmed to incorporate peptide sequences to achieve a remarkable range of bioactivities. Here, the influence of peptide sequence and chirality on micelle structure and interactions is investigated in a series of lipopeptides bearing two lysine or D-lysine residues and tyrosine or tryptophan residues, attached to a hexadecyl lipid chain. All molecules self-assemble into micelles above a critical micelle concentration (CMC). Small-angle x-ray scattering (SAXS) is used to probe micelle shape and structure from the form factor and to probe inter-micellar interactions via analysis of structure factor. The CMC is obtained consistently from surface tension and electrical conductivity measurements. We introduce a method to obtain the zeta potential from the SAXS structure factor which is in good agreement with directly measured values. Atomistic molecular dynamics simulations provide insights into molecular packing and conformation within the lipopeptide micelles which constitute model self-assembling colloidal systems and biomaterials.

Surface Structure of Lecithin-Capped Cesium Lead Halide Perovskite Nanocrystals Using Solid-State and Dynamic Nuclear Polarization NMR Spectroscopy.

Inorganic colloidal cesium lead halide perovskite nanocrystals (NCs) encapsulated by surface capping ligands exhibit tremendous potential in optoelectronic applications, with their surface structure playing a pivotal role in enhancing their photophysical properties. Soy lecithin, a tightly binding zwitterionic surface-capping ligand, has recently facilitated the high-yield synthesis of stable ultraconcentrated and ultradilute colloids of CsPbX3 NCs, unlocking a myriad of potential device applications. However, the atomic-level understanding of the ligand-terminated surface structure remains uncertain. Herein, we use a versatile solid-state nuclear magnetic resonance (NMR) spectroscopic approach, in combination with dynamic nuclear polarization (DNP) and atomistic molecular dynamics (MD) simulations, to explore the effect of lecithin on the core-to-surface structures of CsPbX3 (X = Cl or Br) perovskites, sized from micron to nanoscale. Surface-selective (cross-polarization, CP) solid-state and DNP NMR (133Cs and 207Pb) methods were used to differentiate the unique surface and core chemical environments, while the head-groups {trimethylammonium [-N(CH3)3+] and phosphate (-PO4-)} of lecithin were assigned via 1H, 13C, and 31P NMR spectroscopy. A direct approach to determining the surface structure by capitalizing on the unique heteronuclear dipolar couplings between the lecithin ligand (1H and 31P) and the surface of the CsPbCl3 NCs (133Cs and 207Pb) is demonstrated. The 1H-133Cs heteronuclear correlation (HETCOR) DNP NMR indicates an abundance of Cs on the NC surface and an intimate proximity of the -N(CH3)3+ groups to the surface and subsurface 133Cs atoms, supported by 1H{133Cs} rotational-echo double-resonance (REDOR) NMR spectroscopy. Moreover, the 1H-31P{207Pb} CP REDOR dephasing curve provides average internuclear distance information that allows assessment of -PO4- groups binding to the subsurface Pb atoms. Atomistic MD simulations of ligand-capped CsPbCl3 surfaces aid in the interpretation of this information and suggest that ligand -N(CH3)3+ and -PO4- head-groups substitute Cs+ and Cl- ions, respectively, at the CsCl-terminated surface of the NCs. These detailed atomistic insights into surface structures can further guide the engineering of various relevant surface-capping zwitterionic ligands for diverse metal halide perovskite NCs.

Diffusion and structure of propylene carbonate-metal salt electrolyte solutions for post-lithium-ion batteries: From experiment to simulation.

The diffusion of cations in organic solvent solutions is important for the performance of metal-ion batteries. In this article, pulsed field gradient nuclear magnetic resonance experiments and fully atomistic molecular dynamic simulations were employed to study the temperature-dependent diffusive behavior of various liquid electrolytes representing 1M propylene carbonate solutions of metal salts with bis(trifluoromethylsulfonyl)imide (TFSI-) or hexafluorophosphate (PF6-) anions commonly used in lithium-ion batteries and beyond. The experimental studies revealed the temperature dependence of the diffusion coefficients for the propylene carbonate (PC) solvent and for the anions following an Arrhenius type of behavior. It was observed that the PC molecules are the faster species. For the monovalent cations (Li+, Na+, K+), the PC solvent diffusion was enhanced as the cation size increased, while for the divalent cations (Mg2+, Ca2+, Sr2+, Ba2+), the opposite trend was observed, i.e., the diffusion coefficients decreased as the cation size increased. The anion diffusion in LiTFSI and NaTFSI solutions was found to be similar, while in electrolytes with divalent cations, a decrease in anion diffusion with increasing cation size was observed. It was shown that non-polarizable charge-scaled force fields could correspond perfectly to the experimental values of the anion and PC solvent diffusion coefficients in salt solutions of both monovalent (Li+, Na+, K+) and divalent (Mg2+, Ca2+, Sr2+, Ba2+) cations at a range of operational temperatures. Finally, after calculating the radial distribution functions between cations, anions, and solvent molecules, the increase in the PC diffusion coefficient established with the increase in cation size for monovalent cations was clearly explained by the large hydration shell of small Li+ cations, due to their strong interaction with the PC solvent. In solutions with larger monovalent cations, such as Na+, and with a smaller solvation shell of PC, the PC diffusion is faster due to more liberated solvent molecules. In the salt solutions with divalent cations, both the anion and the PC diffusion coefficients decreased as the cation size increased due to an enhanced cation-anion coordination, which was accompanied by an increase in the amount of PC in the cation solvation shell due to the presence of anions.

Influence of perturbative intertube interactions on ballistic and quasi-ballistic phonon transports in double-walled carbon nanotubes

Assembling single-walled carbon nanotubes (SWCNT) into multiwalled carbon nanotubes (MWCNT) reduces the intrinsically high thermal conductivity of individual SWCNTs. Typically, this reduction can be explained by structural imperfections, e.g., defects, and van der Waals (vdW) intertube interactions between the constituent SWCNTs are considered to have negligible impacts on the reduction. However, intertube interactions should alter the transport characteristics of low-frequency phonons responsible for heat conduction, which implies that intertube interactions may also reduce the thermal conductivity of MWCNTs when low-frequency phonons modulated by intertube interactions participate in the overall heat conduction. In this study, by applying a combination of the atomistic Green's function method and nonequilibrium molecular dynamics simulation to double-walled carbon nanotubes (DWCNT) with different chiral configurations of SWCNTs and various lengths, we investigated the length scale and chiral configuration where perturbative intertube interactions can suppress phonon transports. We found that thermal resistance attributed to intertube interactions manifests in the low-temperature ballistic regime and quasi-ballistic regime for DWCNT lengths greater than 1 μm. Revisiting the influence of the intertube interactions helps comprehend the intrinsic origin of the reduced thermal conductivity of MWCNTs. In addition, the reported findings are beneficial for the thermal engineering of SWCNT-assembled materials, including emerging one-dimensional vdW heterostructures.

Nature of TiO2–oligonucleotides interactions by atomistic molecular dynamics simulations

We used molecular dynamics simulations to investigate the adsorption behavior of single-stranded deoxyribonucleic acid (ssDNA) segments on the anatase (101) surface. Four different ssDNA oligonucleotides, each consisting of six/twelve adenine (A6 and A12), six guanine (G6), six cytosine (C6) or six/twelve thymine (T6 and T12) nucleobases, were considered. We observed that the initial interaction between the ssDNA and the surface occurs primarily through hydrogen bonding between the nucleobases and the surface, followed by strong chemical bonding between the terminal phosphate group and the anatase surface. The interactions between the nucleobases and the surface varied between the different ssDNA segments. Adenine showed the highest affinity for the surface, whereas thymine showed the lowest affinity. In addition, the purine bases interact more strongly when the surface is negatively charged (as it would be at physiological pH) than in neutral surface (slightly acidic conditions), in agreement with experimental data from fluorescence experiments and ATR-FTIR spectroscopy. Moreover, our study provides mechanistic insights into the dynamic behavior of ssDNA on the anatase surface and comparative analyses on how different conditions (pH, fragment length, composition, etc.) affect DNA/TiO2 interactions. Therefore, we expect that experimental scientists will benefit from our work in the design of optimal nanoconjugates for their specific final goals and applications.

Alleviating internal stress in diamond-like carbon films for enhanced tribological performance under high contact pressure via interface texturing

Diamond-like carbon (DLC) films have found widespread applications across numerous fields due to their exceptional properties. Nevertheless, their significant internal stress has restricted their further utility, particularly in scenarios involving high-contact pressure conditions. In response to this challenge, we fabricated diamond-like carbon films with nano-depth interface texture. This nano-depth interface texturing technique helps alleviate the internal stress within the carbon film, thereby enhancing the tribological performance of diamond-like carbon films with textured interfaces, especially under high contact pressure. We successfully fabricated textured carbon films with a thickness of 1 μm, which exhibited excellent tribological performance even under pressures exceeding 1 GPa. Through atomistic molecular dynamics simulations, internal stress testing, and cross-sectional transmission electron microscopy imaging, we observed that the incorporation of nano-depth interface texturing resulted in an approximate 47.62 % increase in the thickness of the transition layer between the silicon substrate and the carbon film. Furthermore, there was a notable reduction of about 30 % in the internal stress exhibited by the carbon films. These findings are expected to expand the application of carbon films under higher contact pressure and facilitate the production of thicker films.

Molecular simulation of understanding the structure and separation thermodynamics of BTX (Benzene, Toluene, Xylene) using amino acid based ionic liquids

The separation of aromatics and aliphatic from the hydrocarbon mixture stands a significant challenge. In this manuscript we present atomistic molecular dynamic simulations to understand the structure and separation thermodynamic properties of BTX (Benzene, toluene, xylene) from n-heptane using ionic liquids. Here we considered the amino acid derived ionic liquid considering the tetra butyl phosphonium as cation and valine anion at three different temperatures 298 K, 323 K and 348 K. We observe that IL show strong intermolecular structure with BEN (benzene) when compared to TOL (toluene) and XYL (p-xylene). Based on the solvation free energy (ΔGsolv), transfer free energy (ΔGtransfer) and partition coefficient (log P) analysis of BEN show favourable for the transfer from n-heptane to IL phase when compared to TOL and XYL. Overall results presented in this paper provide molecular level understanding of the design of amino acid-based IL for the separation BTX from the hydrocarbon mixture.

Minimal Peptide Sequences That Undergo Liquid-Liquid Phase Separation via Self-Coacervation or Complex Coacervation with ATP.

The simple (self-)coacervation of the minimal tryptophan/arginine peptide sequences W2R2 and W3R3 was observed in salt-free aqueous solution. The phase diagrams were mapped using turbidimetry and optical microscopy, and the coacervate droplets were imaged using confocal microscopy complemented by cryo-TEM to image smaller droplets. The droplet size distribution and stability were probed using dynamic light scattering, and the droplet surface potential was obtained from zeta potential measurements. SAXS was used to elucidate the structure within the coacervate droplets, and circular dichroism spectroscopy was used to probe the conformation of the peptides, a characteristic signature for cation-π interactions being present under conditions of coacervation. These observations were rationalized using a simple model for the Rayleigh stability of charged coacervate droplets, along with atomistic molecular dynamics simulations which provide insight into stabilizing π-π stacking interactions of tryptophan as well as arginine-tryptophan cation-π interactions (which modulate the charge of the tryptophan π-electron system). Remarkably, the dipeptide WR did not show simple coacervation under the conditions examined, but complex coacervation was observed in mixtures with ATP (adenosine triphosphate). The electrostatically stabilized coacervation in this case provides a minimal model for peptide/nucleotide membraneless organelle formation. These are among the simplest model peptide systems observed to date able to undergo either simple or complex coacervation and are of future interest as protocell systems.

Temperature dependence of the near infrared absorption spectrum of single-wall carbon nanotubes dispersed by sodium dodecyl sulfate in aqueous solution: experiments and molecular dynamics study.

Single-wall carbon nanotubes (SWCNT) dispersed in water with the help of sodium dodecyl sulfate (SDS) surfactants exhibit a temperature dependent near infrared (NIR) exciton spectrum. Due to their biocompatibility and NIR spectrum falling within the transparent window for biological tissue, SWCNTs hold potential for sensing temperature inside cells. Here, we seek to elucidate the mechanism responsible for this temperature dependence, focusing on changes in the water coverage of the SWCNT as the surfactant structure changes with temperature. We compare optical absorption spectra in the UV-Vis-IR range and fully atomistic molecular dynamics (MD) simulations. The observed temperature dependence of the spectra for various SWCNTs may be attributed to changes in the dielectric environment and its impact on excitons. MD simulations reveal that the adsorbed SDS molecules effectively shield the SWCNT, with ~ 70% of water molecules removed from the first two adlayers; this coverage shows a modest temperature dependence. Although we are not able to directly demonstrate how this influences the NIR spectrum, this represents a potential pathway given the strong influence of the water environment on the excitons in SWCNTs. Optical absorption measurements were carried out in the UV-Vis-NIR range using a Varian Cary 5000 spectrophotometer in a temperature-controlled environment. PeakFit™ v. 4.06 was used as peak-fitting program in the spectral range 900-1400nm (890-1380meV) as a function of the temperature. Fully atomistic molecular dynamics simulations were conducted using the NAMD2 package. The CHARMM force field comprising two-body bond stretching, three-body angle deformation, four-body dihedral angle deformation, and nonbonded interactions (electrostatic and Lennard-Jones 6-16 potentials) was employed.

MDavocado: Analysis and Visualization of Protein Motion by Time-Dependent Angular Diagrams.

Extracting meaningful information from atomistic molecular dynamics (MD) simulations of proteins remains a challenging task due to the high-dimensionality and complexity of the data. MD simulations yield trajectories that contain the positions of thousands of atoms in millions of steps. Gaining a comprehensive understanding of local dynamical events across the entire trajectory is often difficult. Here, we present a novel approach to visualize MD trajectories in the form of time-dependent Ramachandran plots. Specialized data aggregation techniques are employed to address the challenge of plotting millions of data points on a single image, thereby ensuring that the analysis is independent of the molecule size and/or length of the MD simulation. This approach facilitates quick identification of flexible and dynamic regions, and its strength is the ability to simultaneously observe the movements of all amino acids over time. The Python program MDavocado is freely available at GitHub (https://github.com/zoranstefanic/MDavocado).

Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition

The Bin/Amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in regulating mitochondrial ultrastructure and ciliogenesis, but its physiological role in the brain remains unclear. Here, we show that FAM92A1 is expressed in neurons starting from embryonic development. FAM92A1 knockout in mice results in altered brain morphology and age-associated cognitive deficits, potentially due to neuronal degeneration and disrupted synaptic plasticity. Specifically, FAM92A1 deficiency impairs diverse neuronal membrane morphology, including the mitochondrial inner membrane, myelin sheath, and synapses, indicating its roles in membrane remodeling and maintenance. By determining the crystal structure of the FAM92A1 BAR domain, combined with atomistic molecular dynamics simulations, we uncover that FAM92A1 interacts with phosphoinositide- and cardiolipin-containing membranes to induce lipid-clustering and membrane curvature. Altogether, these findings reveal the physiological role of FAM92A1 in the brain, highlighting its impact on synaptic plasticity and neural function through the regulation of membrane remodeling and endocytic processes.

Multiple Functional Protein-Protein Interaction Interfaces Allosterically Regulate ATP-Binding in Cyclin-Dependent Kinase-1.

The ATP-dependent phosphorylation activity of cyclin-dependent kinase 1 (CDK1), an essential enzyme for cell cycle progression, is regulated by interactions with Cyclin-B, substrate, and Cks proteins. We have recently shown that active site acetylation in CDK1 abrogated binding to Cyclin-B which posits an intriguing long-range communication between the catalytic site and the protein-protein interaction (PPI) interface. Now, we demonstrate a general allosteric link between the CDK1 active site and all three of its PPI interfaces through atomistic molecular dynamics (MD) simulations. Specifically, we examined ATP binding free energies to CDK1 in native nonacetylated (K33wt) and acetylated (K33Ac) forms as well as the acetyl-mimic K33Q and the acetyl-null K33R mutant forms, which are accessible in vitro. In agreement with experiments, ATP binding is stronger in K33wt relative to the other three perturbed states. Free energy decomposition reveals, in addition to expected local changes, significant and selective nonlocal entropic responses to ATP binding/perturbation of K33 from the -helix, activation loop (A-loop), and - H segments in CDK1 which interface with Cyclin-B, substrate, and Cks proteins, respectively. Statistical analysis reveals that while entropic responses of protein segments to active site perturbations are on average correlated with their dynamical changes, such correlations are lost in about 9%-48% of the dataset depending on the segment. Besides proving the bi-directional communication between the active site and the CDK1:Cyclin-B interface, our study uncovers a hitherto unknown mode of ATP binding regulation by multiple PPI interfaces in CDK1.

Repairing surface defects of carbon fibers: Electrostatic spraying nano-carbons on stabilized PAN-fibers and subsequent thermal annealing

The introducing of nanomaterials on the carbon fibers (CFs) surface is an effective method for repairing surface defects. Due to the chemical inertness of CFs surface, the bonding force between reinforcing material and CFs is weak. In this paper, nano-carbons (graphene oxide and graphene quantum dots) were assembled to defects on surface of stabilized fibers (SFs) through electrostatic spraying assisted by airflow and then thermally annealed to enhance bonding force between nano-carbons and fibers. The distribution of nano-carbons on fibers surface was explored and it was found that the nano-carbons were directionally covered on or filled in defects on fibers surface to reduce specific surface area and pore volume. The chemical structures on fiber surface were discussed by X-ray photoelectron spectroscopy and atomistic ReaxFF molecular dynamics simulation, and it suggested that covalent crosslinking occurred between CFs surface and nano-carbons. And further, the nano-scratch on fibers surface revealed a significant increase in the bonding force between nano-carbons and fiber after thermal annealing. The maximum tensile strength and Young´s modulus of CFs with nano-carbons increased 24.36% and 38.63%, respectively. Subsequently, the finite element simulation ABAQUS was adopted to demonstrate that the addition of nano-carbons alleviated stress concentration at defects on CFs surface. At the same time, the smaller stress and stress diffusion were found in CFs reinforced by graphene oxide than that with graphene quantum dots.

Lipid Organization by the Caveolin-1 Complex.

Caveolins are lipid-binding proteins that can organize membrane remodeling and oligomerize into the 8S-complex. The CAV1 8S-complex comprises a disk-like structure, about 15nm in diameter, with a central beta barrel. Further oligomerization of 8S-complexes remodels the membrane into caveolae vessels, with a dependence on cholesterol concentration. However, the molecular mechanisms behind membrane remodeling and cholesterol filtering are still not understood. Performing atomistic Molecular Dynamics simulations in combination with advanced sampling techniques, we describe how the CAV1-8S complex bends the membrane and accumulates cholesterol. Here, our simulations show an enhancing effect by the palmitoylations of CAV1, and we predict that the CAV1-8S complex can extract cholesterol molecules from the lipid bilayer and accommodate them in its beta barrel. Through backmapping to the all-atom level we also conclude that the Martini v2 coarse-grained forcefield overestimates membrane bending, as the atomistic simulations exhibit only very localized bending.