Design and Characterization of Antibacterial Peptide Nanofibrils as Components of Composites for Biomaterial Applications.

Volume can provide informative structural descriptions of macromolecules such as proteins in solution because a final volumetric outcome accompanies the exquisite equipoise of packing effects between residues, and residues and waters inside and outside proteins. Here we performed systematic investigations on the volumetric nature of the amyloidogenic conformations of beta2-microglobulin (beta2-m) and its amyloidogenic core peptide, K3, using a high precision densitometer. The transition from the acid-denatured beta2-m to the mature amyloid fibrils was accompanied by a positive change in the partial specific volume, which was larger than that observed for the transition from the acid-denatured beta2-m to the native structure. The data imply that the mature amyloid fibrils are more voluminous than the native structure because of a sparse packing density of side chains. In contrast, the formation of the mature amyloid-like fibrils of the K3 from the random coil was followed by a considerable decrease in the partial specific volume, suggesting a highly compact core structure. Interestingly, the immature amyloid-like fibrils of beta2-m exhibited a volume intermediate between those of the mature fibrils of beta2-m and K3, because of the core structure at their center and the relatively noncompact region around the core with much hydration. These volumetric differences would result from the nature of main-chain-dominated fibrillogenesis. We suggest comprehensive models for these three types of fibrils illustrating packing and hydrational states.

The mobility of simple ions such as alkali–metal and halide ions at room temperature shows two anomalies. Firstly, there are maxima in mobilities as a function of ion size for both positive and negative ions and, secondly, the maximum for negative ions occurs at a larger ionic radius than the maximum for positive ions. Theoretical treatments of this problem are reviewed and it is concluded that a molecular treatment of the system is needed to understand the results. Computer simulation using the simple point charge model (SPC/E) for water reproduced the observations and is used to discuss the application of theories. In particular, the nature of the first solvation shell is correlated with ion mobility. Simulation reveals a further anomaly, namely that if the charge is removed from a large ion, then it moves more slowly. This is interpreted as the result of formation of a solvent cage around the hydrophobic solute. The changes in local structure resulting from changes in charge and size also affect the solvation thermodynamics. Simulations show that the solvation entropy has a double maximum when viewed as a function of charge. The local minimum near zero charge is interpreted as being due to hydrophobic order, and the maxima as the result of structure breaking. This double maximum in the entropy of solvation is a signature of the hydrophobic cage effect. Comparisons are made between ion mobilities in liquid water at ambient and supercritical conditions.

The virial stress is the most commonly used definition of stress in discrete particle systems. This quantity includes two parts. The first part depends on the mass and velocity (or, in some versions, the fluctuation part of the velocity) of atomic particles, reflecting an assertion that mass transfer causes mechanical stress to be applied on stationary spatial surfaces external to an atomic‐particle system. The second part depends on interatomic forces and atomic positions, providing a continuum measure for the internal mechanical interactions between particles. Historic derivations of the virial stress include generalization from the virial theorem of Clausius (1870) for gas pressure and solution of the spatial equation of balance of momentum. The virial stress is stress‐like a measure for momentum change in space. This paper shows that, contrary to the generally accepted view, the virial stress is not a measure for mechanical force between material points and cannot be regarded as a measure for mechanical stress in any sense. The lack of physical significance is both at the individual atom level in a time‐resolved sense and at the system level in a statistical sense. It is demonstrated that the interatomic force term alone is a valid stress measure and can be identified with the Cauchy stress. The proof in this paper consists of two parts. First, for the simple conditions of rigid translation, uniform tension and tension with thermal oscillations, the virial stress yields clearly erroneous interpretations of stress. Second, the conceptual flaw in the generalization from the virial theorem for gas pressure to stress and the confusion over spatial and material equations of balance of momentum in theoretical derivations of the virial stress that led to its erroneous acceptance as the Cauchy stress are pointed out. Interpretation of the virial stress as a measure for mechanical force violates balance of momentum and is inconsistent with the basic definition of stress. The versions of the virial‐stress formula that involve total particle velocity and the thermal fluctuation part of the velocity are demonstrated to be measures of spatial momentum flow relative to, respectively, a fixed reference frame and a moving frame with a velocity equal to the part of particle velocity not included in the virial formula. To further illustrate the irrelevance of mass transfer to the evaluation of stress, an equivalent continuum (EC) for dynamically deforming atomistic particle systems is defined. The equivalence of the continuum to discrete atomic systems includes (i) preservation of linear and angular momenta, (ii) conservation of internal, external and inertial work rates, and (iii) conservation of mass. This equivalence allows fields of work‐ and momentum‐preserving Cauchy stress, surface traction, body force and deformation to be determined. The resulting stress field depends only on interatomic forces, providing an independent proof that as a measure for internal material interaction stress is independent of kinetic energy or mass transfer.

The bacterial SecYEG translocon functions as a conserved protein-conducting channel. Conformational transitions of SecYEG allow protein translocation across the membrane without perturbation of membrane permeability. Here, we report the crystal structures of intact SecYEG at 2.7-Å resolution and of peptide-bound SecYEG at 3.6-Å resolution. The higher-resolution structure revealed that the cytoplasmic loop of SecG covers the hourglass-shaped channel, which was confirmed to also occur in the membrane by disulfide bond formation analysis and molecular dynamics simulation. The cytoplasmic loop may be involved in protein translocation. In addition, the previously unknown peptide-bound crystal structure of SecYEG implies that interactions between the cytoplasmic side of SecY and signal peptides are related to lateral gate opening at the first step of protein translocation. These SecYEG structures therefore provide a number of structural insights into the Sec machinery for further study.

Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.

It is widely believed that Alzheimer's disease pathogenesis is driven by the production and deposition of the amyloid-β peptide (Aβ) in the brain. In this study, we employ a combination of in silico and in vitro approaches to investigate the inhibitory properties of selected arginine-rich D-enantiomeric peptides (D-peptides) against amyloid aggregation. The D-peptides include D3, a 12-residue peptide with anti-amyloid potencies demonstrated in vitro and in vivo, RD2, a scrambled sequence of D3, as well as truncated RD2 variants. Using a global optimization method together with binding free energy calculations followed by molecular dynamics simulations, we perform a detailed analysis of D-peptide binding to Aβ monomer and a fibrillar Aβ structure. Results obtained from both molecular simulations and surface plasmon resonance experiments reveal a strong binding of D3 and RD2 to Aβ, leading to a significant reduction in the amount of β structures in both monomer and fibril, which was also demonstrated in Thioflavin T assays. The binding of the D-peptides to Aβ is driven by electrostatic interactions, mostly involving the D-arginine residues and Glu11, Glu22 and Asp23 of Aβ. Furthermore, we show that the anti-amyloid activities of the D-peptides depend on the length and sequence of the Dpeptide, its ability to form multiple weak hydrophobic interactions with Aβ, as well as the Aβ oligomer size.

Our recent studies revealed that none of the selected widely used force field parameters and molecular dynamics simulation techniques yield structural properties for the intrinsically disordered α-synuclein that are in agreement with various experiments via testing different force field parameters. Here, we extend our studies on the secondary structure properties of the disordered amyloid-β(1-40) peptide in aqueous solution. For these purposes, we conducted extensive replica exchange molecular dynamics simulations and obtained extensive molecular dynamics simulation trajectories from David E. Shaw group. Specifically, these molecular dynamics simulations were conducted using various force field parameters and obtained results are compared to our replica exchange molecular dynamics simulations and experiments. In this study, we calculated the secondary structure abundances and radius of gyration values for amyloid-β(1-40) that were simulated using varying force field parameter sets and different simulation techniques. In addition, the intrinsic disorder propensity, as well as sequence-based secondary structure predisposition of amyloid-β(1-40) and compared the findings with the results obtained from molecular simulations using various force field parameters and different simulation techniques. Our studies clearly show that the epitope region identification of amyloid-β(1-40) depends on the chosen simulation technique and chosen force field parameters. Based on comparison with experiments, we find that best computational results in agreement with experiments are obtained using the a99sb*-ildn, charmm36m, and a99sb-disp parameters for the amyloid-β(1-40) peptide in molecular dynamics simulations without parallel tempering or via replica exchange molecular dynamics simulations.

The influence of the microstructure of polycarbonate (PC) on performance was systematically investigated by both experimental method and molecular simulation. Yield stress, impact strength, molecular weight, and transmittance were used to distinguish the degradation processes between different PCs, and thermal degradation kinetics was studied to obtain the activation energy. At the molecular level, through 13C nuclear magnetic resonance (NMR) spectroscopy, it was observed that PCs have a more polar group of benzene rings, resulting in the high density, dielectric constant, and tensile modulus. Meanwhile, molecular dynamics (MD) simulation was employed under a polymer consistent force field force field. Specific volume and mechanical property were analyzed to investigate the thermodynamic property. The molecular dynamics simulation and experimental results on half decomposition temperature (T1/2), refraction index, flow activation energy, average density, cohesive energy density, glass transition temperature (Tg), and elastic modulus had good agreement. Therefore, it was indicated that the molecular simulation could successfully study the characteristics and properties. The fundamental studies would be expected to supply useful information for designing materials and optimizing processing technology.

Protein conformational transition from alpha-helices to beta-sheets precedes aggregation of proteins implicated in many diseases, including Alzheimer and prion diseases. Direct characterization of such transitions is often hindered by the complicated nature of the interaction network among amino acids. A recently engineered small protein-like peptide with a simple amino acid composition features a temperature-driven alpha-helix to beta-sheet conformational change. Here we studied the conformational transition of this peptide by molecular dynamics simulations. We observed a critical temperature, below which the peptide folds into an alpha-helical coiled-coil state and above which the peptide misfolds into beta-rich structures with a high propensity to aggregate. The structures adopted by this peptide during low temperature simulations have a backbone root mean square deviation less than 2 A from the crystal structure. At high temperatures, this peptide adopts an amyloid-like structure, which is mainly composed of coiled anti-parallel beta-sheets with the cross-beta-signature of amyloid fibrils. Most strikingly, we observed conformational conversions in which an alpha-helix is converted into a beta-strand by proximate stable beta-sheets with exposed hydrophobic surfaces and unsaturated hydrogen bonds. Our study suggested a possible generic molecular mechanism of the template-mediated aggregation process, originally proposed by Prusiner (Prusiner, S. B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 13363-13383) to account for prion infectivity.

Molecular simulations are powerful tools for revealing the properties of polymers at the molecular level. In particular, coarse-grained molecular dynamics simulations are useful for elucidating the deformation and fracture processes of polymers. However, in the case of crystalline polymers, it is difficult to reproduce experimentally observed structures and mechanical properties using these models. This review describes our recent investigations into the deformation and fracture processes of crystalline polymers using coarse-grained molecular dynamics simulations. We were able to successfully reproduce the lamellar structure of polyethylene, which is a fundamental structural feature of this polymer, and obtain a stress–strain curve that exhibited good consistency with that observed experimentally. The molecular dynamics simulations revealed that void generation in the amorphous layers was caused by the movement of the chain ends, which is difficult to observe through experiments. The conditions required to reproduce the experimentally observed structure and mechanical properties using molecular simulations are also discussed. In this focus review, our recent investigations into the deformation and fracture processes of crystalline polymers using coarse-grained molecular dynamics simulations are described. The lamellar structure of polyethylene, a fundamental structural feature of this polymer, is successfully reproduced. Then, a stress– strain curve that exhibited good consistency with that observed experimentally is obtained. Molecular simulations are a powerful tool for elucidating the mechanisms of the deformation and fracture processes of crystalline polymers at the molecular level and this review will contribute to the development of this field of research.

Source rocks contain significant volumes of hydrocarbon fluids trapped in kerogen, however their effective recovery is challenged due to amplified fluid-wall interactions and the nanopore confinement impact on fluid composition. Enhanced oil production can be achieved by modifying the existing molecular forces in kerogen pore-network by using custom-designed targeted chemistry technologies. Our objective is to show how the transport of hydrocarbons in kerogen and its recovery can be altered with the delivery of microemulsion nanodroplets into the pore network. This is done by using computational chemistry and molecular dynamics (MD) simulations. Molecular dynamics simulation is used to generate a 3D model replica of a Type II kerogen representative of source rocks located in Delaware and Midland basins in the United States. Oil phase saturated kerogen is modeled as consisting of nine different types of molecules: dimethyl naphthalene, toluene, tetradecane, decane, octane, butane, propane, ethane and methane. The delivered microemulsion is an aqueous dispersion of solvent-swollen surfactant micelles. The solvent and nonionic surfactant present in the microemulsion are modeled as d-limonene and dodecanol heptaethyl ether (C12E7), respectively. Molecular dynamics simulation experiments include two steps: (i) the injection of microemulsion treatment fluid into the oil-saturated kerogen pore-network, and (ii) transient flow-back of the oil-chemical mixture in the pore network. The utilized 3D kerogen models were developed based on a representative oil sample composition (H, C, O, S, N) from the region. Simulation results show that microemulsions can affect the reservoir via two different mechanisms. During the injection, microemulsion nanodroplets that enter the nano-capillaries of pore network disperse in the liquid present in the pore space under the influence of pore walls. The solvent dissolves in the oil phase and alters the physical and transport properties of the phase, while the surfactant molecules modify the wettability of the solid kerogen surfaces. The recovery effectiveness of heavier oil fractions is improved compared to the recovery effectiveness achieved with surfactant micelles without the solubilized solvent. New 3D kerogen models are presented using atomistic modeling and molecular simulations. These models possess important chemical and physical characteristics of the organic matter of the source rock. Molecular dynamic experiments indicate that solubilized solvent and surfactant are delivered as part of a microemulsion droplet and are expected to aid the mobilization of oil present within kerogen.

Fluorescence spectroscopy and molecular simulation were explored to study the interaction between caffeic acid and human serum albumin (HSA). The experimental results indicated that the fluorescence quenching mechanism between caffeic acid and HSA is a static quenching, which was proved again by the analysis of fluorescence lifetime by time-correlated single photon counting. The binding process is spontaneous and the hydrophobic force is the main force between caffeic acid and HSA. In addition, the binding of caffeic acid to HSA was modeled by molecular dynamics simulations. The root mean square deviations, root mean square fluctuations, radius of gyration and the number of hydrogen bonds of the molecular dynamic (MD) simulation process were analyzed. Both experimental and modeling results demonstrated strong binding between HSA and caffeic acid. HSA had a slight conformational change when it binds with caffeic acid. The obtained information is useful for HSA drug design. Copyright © 2016 John Wiley & Sons, Ltd.

Molecular dynamics simulation as a tool for prediction of the properties of TiO2 and TiO2:MoO3 based chemical gas sensors

The escalating threat posed by the Monkeypox virus (MPXV) to global health necessitates the urgent discovery of effective antiviral agents, as there are currently no specific drugs available for its treatment, and existing inhibitors are hindered by toxicity and poor pharmacokinetic profiles. This study aimed to identify potent MPXV inhibitors by screening a diverse library of small molecule compounds derived from marine fungi, focusing on the viral protein VP39, a key methyltransferase involved in viral replication. An extensive virtual screening process identified four promising compounds—CMNPD15724, CMNPD28811, CMNPD30883, and CMNPD18569—alongside a control molecule. Rigorous evaluations, including re-docking, molecular dynamics (MD) simulations, and hydrogen bond analysis, were conducted to assess their inhibitory potential against MPXV VP39. CMNPD15724 and CMNPD30883, in particular, demonstrated a superior binding affinity and stable interactions within the target protein's active site throughout the MD simulations, suggesting a capacity to overcome the limitations associated with sinefungin. The stability of these VP39-compound complexes, corroborated by MD simulations, provided crucial insights into the dynamic behavior of these interactions. Furthermore, Principal Component Analysis (PCA) based free energy landscape assessments offered a detailed understanding of the dynamic conformational changes and energetic profiles underlying these compounds' functional disruption of VP39. These findings establish CMNPD15724, CMNPD28811, CMNPD30883, and CMNPD18569 as promising MPXV inhibitors and highlight marine fungi as a valuable source of novel antiviral agents. These compounds represent potential candidates for further experimental validation, advancing the development of safer and more effective therapeutic options to combat this emerging viral infection.

SummaryThe mechanism of T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCRβ or CD3ζ that augment peptide T cell antigen receptor (pMHC)-induced signaling not explicable by enhanced ligand binding, lateral diffusion, clustering, or co-receptor function. Using a biochemical assay and molecular dynamics simulation, we demonstrate that the gain-of-function mutations loosen the interaction between TCRαβ and CD3ζ. Similar to the activating mutations, pMHC binding reduces TCRαβ cohesion with CD3ζ. This event occurs prior to CD3ζ phosphorylation and at 0°C. Moreover, we demonstrate that soluble monovalent pMHC alone induces signaling and reduces TCRαβ cohesion with CD3ζ in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCRαβ to the CD3 subunits, reconfiguring interchain transmembrane region interactions. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to license CD3ζ phosphorylation and initiate signal propagation.