The influence of static stress and alternating loading direction on the potential energy and mechanical properties of amorphous alloys is investigated using molecular dynamics simulations. The model glass is represented via a binary mixture which is first slowly annealed well below the glass transition temperature and then subjected to elastostatic loading either along a single direction or along two and three alternating directions. We find that at sufficiently large values of the static stress, the binary glass becomes rejuvenated via collective, irreversible rearrangements of atoms. Upon including additional orientation of the static stress in the loading protocol, the rejuvenation effect is amplified and the typical size of clusters of atoms with large nonaffine displacements increases. As a result of prolonged mechanical loading, the elastic modulus and the peak value of the stress overshoot during startup continuous compression become significantly reduced, especially for loading protocols with alternating stress orientation. These findings are important for the design of novel processing methods to improve mechanical properties of metallic glasses.
The influence of variable-amplitude loading on the potential energy and mechanical properties of amorphous materials is investigated using molecular dynamics simulations. We study a binary mixture that is either rapidly or slowly cooled across the glass transition temperature and then subjected to a sequence of shear cycles with strain amplitudes above and below the yielding strain. It was found that well annealed glasses can be rejuvenated by small-amplitude loading if the strain amplitude is occasionally increased above the critical value. By contrast, poorly annealed glasses are relocated to progressively lower energy states when subyield cycles are alternated with large-amplitude cycles that facilitate exploration of the potential energy landscape. The analysis of nonaffine displacements revealed that in both cases, the typical size of plastic rearrangements varies depending on the strain amplitude and number of cycles, but remains smaller than the system size, thus preserving structural integrity of amorphous samples.
Mal de Meleda is an autosomal recessive palmoplantar keratoderma associated with mutations in a gene encoding SLURP-1. SLURP-1 controls growth, differentiation, and apoptosis of keratinocytes by interaction with α7-type nicotinic acetylcholine receptors. SLURP-1 has a three-finger structure with a β-structural core (head) and three prolonged loops (fingers). To determine the role of SLURP-1 mutations, we produced 22 mutant variants of the protein, including those involved in Mal de Meleda pathogenesis. All mutants except R71H, R71P, T52A, R96P, and L98P were produced in the folded form. SLURP-1 reduces the growth of Het-1A keratinocytes; thus, we studied the influence of the mutations on its antiproliferative activity. Mutations in loops I and III led to the protein inactivation, whereas most mutations in loop II increased SLURP-1 antiproliferative activity. Alanine substitutions of R96 and L98 residues located in the protein head resulted in the appearance of additional pro-apoptotic activity. Our results agree with the diversity of Mal de Meleda phenotypes. Using obtained functional data, the SLURP-1/α7 type nicotinic acetylcholine receptor complex was modeled in silico. Our study provides functional and structural information about the role of the SLURP-1 mutations in Mal de Meleda pathogenesis and predicts SLURP-1 variants, which could drive the disease.
An effect of the collective motions on the variance of diffusivity in liquids is considered. It is shown theoretically and with simulation that collective fluctuations increase statistical uncertainty of diffusivity in liquids. On this basis we develop approach that combines molecular dynamics and theoretical models to calculate diffusion coefficient in liquids. We decompose diffusivity into a low scale molecular part and a large scale hydrodynamic part. The low scale term is calculated with the molecular dynamics. It is performed using a small simulation box with less than 100 particles. Local molecular motions appear in such simulations while collective hydrodynamical fluctuations are absent. The large scale hydrodynamics is included with a theoretical model. Thus, molecular dynamics term includes only molecular processes such as rearrangements of molecules, and hydrodynamical term includes collective processes. This approach provides lower statistical uncertainty compared with simulations of large systems. The improvement in statistical accuracy is shown theoretically and confirmed with simulations. It is connected to the relation between diffusivity due to local molecular processes and diffusivity due to hydrodynamics. To illustrate the application of this approach, we compute the self-diffusion coefficient in Lennard-Jones liquid and liquid water, diffusivity of divalent ions in aqueous solutions.
On the basis of computational and experimental approaches, we provide molecular-level insights into melamine cyanurate (M-CA) self-assembly in aqueous solution and identify corresponding mechanisms of aggregation. Our analysis implies that small M-CA molecular complexes are stabilized predominantly via aromatic π–π-stacking rather than by formation of hydrogen bonds. We demonstrate that variation of the [M]/[CA] component concentration ratio results in a smooth change in the structure of the critical nuclei from more disordered in the excess of M to more crystal-like in the excess of CA. This behavior can indicate that the process of M-CA nucleation in aqueous solutions could be altered between classical and nonclassical mechanisms depending on the local [M]/[CA] concentration ratio, which could be prospective for the programmable design of functional supramolecular materials.
The equilibrium and metastable states of the Lennard-Jones vapor, liquid, and crystal, are studied in the vicinity of the phase transition points. Vapor-liquid, liquid-vapor, liquid-crystal, and crystal-liquid transitions are modeled within the molecular dynamics method. As a research tool, a four-point correlation function is used for the qualitative detection of collective motions of atoms in the equilibrium and metastable states. We use its modification, a correlation coefficient, and find singularities at the transition from equilibrium to metastable states. The nature of these changes, as precursors of nucleation, is discussed.
Using molecular dynamics simulation and evolutionary metadynamic calculations, a series of structures were revealed that possessed enthalpies and Gibbs energies lower than those of aragonite but higher than those of calcite. The structures are polytypes of calcite, differing in the stacking sequence of close-packed (cp) Ca layers. The two- and six-layered polytypes have hexagonal symmetry P6322 and were named hexarag and hexite, respectively. Hexarag is similar to aragonite, but with all the triangles placed on the middle distance between the cp layers. On the basis of the structures found, a two-step mechanism for the transformation of aragonite to calcite is suggested. In the first step, CO3 triangles migrate to halfway between the Ca layers with the formation of hexarag. In the second step, the two-layered cp (hcp) hexarag structure transforms into three-layered cp (fcc) calcite through a series of many …
In this paper, we simulate the nucleation and growth of crystalline nuclei in a molybdenum film cooled at different rates confined between two amorphous walls. We also compare the results for the wall-confined and wall-free systems. We apply the same methodology as in the work (Kirova and Pisarev 2019 J. Cryst. Growth 528 125266) which is based on reconstructing the probability density function for the largest crystalline nucleus in the system. The size of the nucleus and the asphericity parameter are considered as the reaction coordinates. We demonstrate that in both the free and confined systems there are two mechanisms of crystal growth: the attachment of atoms to the biggest crystal from the amorphous phase and the merging of the biggest crystal cluster with small ones (coalescence). We show that the attachment mechanism is dominant in the melt cooled down at a slower rate, and the mechanism gradually shifts to coalescence as cooling rate increases. We also observe the formation of long-lived crystal clusters and demonstrate that amorphous walls do not affect their geometric characteristics. However, system confined between walls demonstrates higher glass-forming ability.
A subsonic flow of a viscous compressible fluid in a two-dimensional channel with small periodic or localized irregularities on the walls for large Reynolds numbers is considered. A formal asymptotic solution with double-deck structure of the boundary layer is constructed. A nontrivial time hierarchy is discovered in the decks. An analysis of the scales of irregularities at which the double-deck structure exists is performed.
ɑ-Hairpinins are a family of plant defense peptides with a common fold presenting two short ɑ-helices stabilized by two invariant S–S-bridges. We have shown previously that substitution of just two amino acid residues in a wheat ɑ-hairpinin Tk-AMP-X2 leads to Tk-hefu-2 that features specific affinity to voltage-gated potassium channels KV1.3. Here, we utilize a combined molecular modeling approach based on molecular dynamics simulations and Protein Surface Topography technique to improve the affinity of Tk-hefu-2 to KV1.3 while preserving its specificity. An important advance of this work compared to our previous studies is transition from the analysis of various physico-chemical properties of an isolated toxin molecule to its consideration in complex with its target, a membrane-bound ion channel. As a result, a panel of computationally designed Tk-hefu-2 derivatives was synthesized and tested against KV1.3. The most active mutant Tk-hefu-10 showed an IC50 of ∼150 nM being >10 times more active than Tk-hefu-2 and >200 times more active than the original Tk-hefu. We conclude that ɑ-hairpinins provide an attractive disulfide-stabilized scaffold for the rational design of ion channel inhibitors. Furthermore, success rate can be considerably increased by the proposed “target-based” iterative strategy of molecular design.
The effect of small-amplitude periodic shear on annealing of a shear band in binary glasses is investigated using molecular dynamics simulations. The shear band is first introduced in stable glasses via periodic shear at a strain amplitude slightly above the critical value, and then samples are subjected to repeated loading during thousands of cycles at smaller amplitudes. It was found that with increasing strain amplitude, the glasses are relocated to deeper potential energy levels, while the energy change upon annealing is not affected by the glass initial stability. The results of mechanical tests indicate that the shear modulus and yield stress both increase towards plateau levels during the first few hundred cycles, and their magnitudes are greater for samples loaded at larger strain amplitudes. The analysis of nonaffine displacements reveals that the shear band breaks up into isolated clusters that gradually decay over time, leading to nearly reversible deformation within the elastic range. These results might be useful for mechanical processing of metallic glasses and additive manufacturing.
For many peripheral membrane-binding proteins (MBPs), especially β-structural ones, the precise molecular mechanisms of membrane insertion remain unclear. In most cases, only the terminal water-soluble and membrane-bound states have been elucidated, whereas potential functionally important intermediate stages are still not understood in sufficient detail. In this study we present one of the first successful attempts to describe step-by-step embedding of the MBP cardiotoxin 2 (CT2) from cobra N. oxiana venom into a lipid bilayer at the atomistic level. CT2 possesses a highly conservative and rigid b-structured three-finger fold shared by many other exogenous and endogenous proteins performing a wide variety of functions. Incorporation of CT2 into the lipid bilayer was analyzed via a 2-μs all-atom molecular dynamics (MD) simulation without restraints. This process was shown to occur over a number of distinct steps, while the geometry of initial membrane attachment drastically differs from the final equilibrated state. In the latter one, the hydrophobic platform (“bottom”) formed by the tips of the three loops is deeply buried into the lipid bilayer. This agrees well with the NMR data obtained earlier for CT2 in detergent micelles. However, the bottom is too bulky to insert itself into the membrane at once. Instead, gradual immersion of CT2 initiated by the loop-1 was observed. This initial binding stage was also demonstrated in a series of MD runs with varying starting orientations of the toxin with respect to the bilayer surface. Apart from non-specific long-range electrostatic attraction and hydrophobic match/mismatch factor, several specific lipid binding sites were identified in CT2. They were shown to promote membrane insertion by engaging in strong interactions with lipid head groups, fine-tuning the toxin-membrane accommodation. We therefore propose that the toxin insertion relies on an interplay of nonspecific and specific interactions, which are determined by the “dynamic molecular portraits” of the two players, the protein and the membrane. The proposed model does not require protein oligomerization for membrane insertion and can be further employed to design MBPs with predetermined properties with regard to particular membrane targets.
The influence of alternating shear orientation and strain amplitude of cyclic loading on yielding in amorphous solids is investigated using molecular dynamics simulations. The model glass is represented via a binary mixture that was rapidly cooled well below the glass transition temperature and then subjected to oscillatory shear deformation. It was shown that periodic loading at strain amplitudes above the critical value first induces structural relaxation via irreversible displacements of clusters of atoms during a number of transient cycles, followed by an increase in potential energy due to the formation of a system-spanning shear band. Upon approaching the critical strain amplitude from above, the number of transient cycles required to reach the yielding transition increases. Interestingly, it was found that when the shear orientation is periodically alternated in two or three dimensions, the number of transient cycles is reduced but the critical strain amplitude remains the same as in the case of periodic shear along a single plane. After the yielding transition, the material outside the shear band continues strain-induced relaxation, except when the shear orientation is alternated in three dimensions and the glass is deformed along the shear band with the imposed strain amplitude every third cycle.
Antibacterial activity of the three-finger toxins from cobra venom, including cytotoxin 3 from N. kaouthia, cardiotoxin-like basic polypeptide A5 from N. naja (CLBP), and alpha-neurotoxin from N. oxiana venom, was investigated. All toxins failed to influence Gram-negative bacteria. The most pronounced activity against Bacillus subtilis was demonstrated by CLBP. The latter is ascribed to the presence of additional Lys-residues within the membrane-binding motif of this toxin.
The previously discovered features of the temperature behaviour of four-point spatial correlators allow us to study transitions to metastable states. Similar integral characteristics simultaneously study microscopic effects (vortex formation and clustering) and the effect of these phenomena on the thermodynamics of the whole system. It is shown that spatial and temporal behaviour of correlators in supercooled liquid samples determine the signs of the glass transition in a system before its relaxation. After the liquid sample is supercooled below a certain boundary, particle motion correlations on the coordination spheres sharply increases, similar to the situation in a crystal. The study was carried out using the EAM model of aluminium using the molecular dynamics method.
Despite the biological significance of insulin signaling, the molecular mechanisms of activation of the insulin receptor (IR) and other proteins from its family remain elusive. Current hypothesis on signal transduction suggests ligand-triggered structural changes in the extracellular domain followed by transmembrane (TM) domains closure and dimerization leading to trans-autophosphorylation and kinase activity in intracellular segments of the receptor. Using NMR spectroscopy, we detected dimerization of isolated TM segments of IR in DPC micelles and observed multiple signals of NH groups of protein backbone possibly corresponding to several dimer conformations. Taking available experimental data as constraints, several atomistic models of dimeric TM domains of IR and insulin-like growth factor 1 (IGF-1R) receptors were elaborated. Molecular dynamics simulations of IR ectodomain revealed noticeable collective movements potentially responsible for closure of the C-termini of FnIII-3 domains and spatial approaching of TM helices upon insulin-induced receptor activation. In addition, we demonstrated that the intracellular part of the receptor does not impose restrictions on the positioning of TM helices in the membrane. Finally, we used two independent structure prediction methods to generate a series of dimer conformations followed by their cluster analysis and dimerization free energy estimation to select the best dimer models. Biological relevance of the later was further tested via comparison of the hydrophobic organization of TM helices for both wild-type receptors and their mutants. Based on these data, the ability of several segments from other proteins to functionally replace IR and/or IGF-1R TM domains was explained.
The development of digital (droplet-based) microfluidic (DMF) devices has received significant attention
due to their importance for chemical and biomedical analyses. The precise control and manipulation of
liquid droplets on a solid substrate is a major requirement for DMF devices. In this study, we propose a
novel strategy to generate continuous droplet motion by combining asymmetric corrugations and
patterned wettability on a vibrating substrate. The time periodic oscillations of the substrate with
asymmetric triangle corrugations provide the input energy to transport a droplet along patterned
stripes. Using dissipative particle dynamic (DPD) simulations, we demonstrate that hydrophobic stripes
on a superhydrophobic substrate create a wettability step, which effectively constrains the droplet
motion along the stripe. Due to the special design of asymmetric triangle corrugations and orientation
of hydrophobic stripes, the proposed strategy enables the transport of multiple droplets with different
initial locations towards a single spot and coalescence into a large droplet. We further identify a
power-law dependence between the droplet velocity and the period of substrate vibration and show
that this function is independent of the droplet size. The proposed droplet transportation strategy can
be potentially useful for the efficient manipulation of liquid droplets in DMF devices.
We present the results of the study of changes in liquid properties during ultrafast cooling. The molecular dynamics (MD) method is used, with aluminum melt as an example. Based on the changes in shear stress autocorrelation functions (SACF) with temperature in an ensemble of MD trajectories, we develop three approaches to the study of melt changes. In the first one, we investigate the asymptotic behavior of SACFs and a sharp increase in the melt viscosity, which is a conventional criterion. In the second approach, we present direct evidence of the transition of a metastable melt to a non-equilibrium state. In the third one, we show the appearance of transverse oscillations in a film of the melt. The most important observation is that all three phenomena occur in the same temperature range. On the basis of the current and the previous work, we conclude that there is a gap between the temperature of the splitting of the second peak of the pair correlation function and the temperature of the transition to a solid-like amorphous state. The splitting of the second peak occurs at a significantly higher temperature and this phenomenon is discussed.
The article presents the energy consumption and efficiency analysis based on the data from three small-size supercomputers installed in JIHT RAS. One system is the air-cooled hybrid supercomputer Desmos with AMD FirePro GPUs and two others are the air-cooled and liquid-cooled segments of the supercomputer Fisher based on AMD Epyc Naples CPUs. To collect data, we implement the same real-time analytics infrastructure on all three supercomputers. We consider classical molecular-dynamics problem as a benchmarking tool. Our results quantify the energy savings that are provided by the GPU-based calculations in compariso with CPU-only calculations and by liquid cooling in comparison with air-cooling. During strong scaling benchmarks, we detect an interesting minimum of energy consumption in the CPU-only case.
Antibiotics (AB) resistance is a major threat to global health, thus the development of novel AB classes is urgently needed. Lantibiotics (i.e. nisin) are natural compounds that effectively control bacterial populations, yet their clinical potential is very limited. Nisin targets membrane-embedded cell wall precursor — lipid II — via capturing its pyrophosphate group (PPi), which is unlikely to evolve, and thus represents a promising pharmaceutical target. Understanding of exact molecular mechanism of initial stages of membrane-bound lipid II recognition by water-soluble nisin is indispensable. Here, using molecular simulations, we demonstrate that the structure of lipid II is determined to a large extent by the surrounding water-lipid milieu. In contrast to the bulk solvent, in the bilayer only two conformational states remain capable of nisin binding. In these states PPi manifests a unique arrangement of hydrogen bond acceptors on the bilayer surface. Such a “pyrophosphate pharmacophore” cannot be formed by phospholipids, which explains high selectivity of nisin/lipid II recognition. Similarly, the “recognition module” of nisin, being rather flexible in water, adopts the only stable conformation in the presence of PPi analogue (which mimics the lipid II molecule). We establish the “energy of the pyrophosphate pharmacophore” approach, which effectively distinguishes nisin conformations that can form a complex with PPi. Finally, we propose a molecular model of nisin recognition module/lipid II complex in the bacterial membrane. These results will be employed for further study of lipid II targeting by antimicrobial (poly)cyclic peptides and for design of novel AB prototypes.