Exploring Structural Insights of Aß42 and α-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit and Explicit Solvent Simulations.

Protein misfolding, aggregation, and fibril formation play a central role in the development of severe neurological disorders, including Alzheimer's and Parkinson's diseases. The structural stability of mature fibrils in these diseases is of great importance, as organisms struggle to effectively eliminate amyloid plaques. To address this issue, it is crucial to investigate the early stages of fibril formation when monomers aggregate into small, toxic, and soluble oligomers. However, these structures are inherently disordered, making them challenging to study through experimental approaches. Recently, it has been shown experimentally that amyloid-ß 42 (Aß42) and α-synuclein (α-Syn) can coassemble. This has motivated us to investigate the interaction between their monomers as a first step toward exploring the possibility of forming heterodimeric complexes. In particular, our study involves the utilization of various Amber and CHARMM force-fields, employing both implicit and explicit solvent models in replica exchange and conventional simulation modes. This comprehensive approach allowed us to assess the strengths and weaknesses of these solvent models and force fields in comparison to experimental and theoretical findings, ensuring the highest level of robustness. Our investigations revealed that Aß42 and α-Syn monomers can indeed form stable heterodimers, and the resulting heterodimeric model exhibits stronger interactions compared to the Aß42 dimer. The binding of α-Syn to Aß42 reduces the propensity of Aß42 to adopt fibril-prone conformations and induces significant changes in its conformational properties. Notably, in AMBER-FB15 and CHARMM36m force fields with the use of explicit solvent, the presence of Aß42 significantly increases the ß-content of α-Syn, consistent with the experiments showing that Aß42 triggers α-Syn aggregation. Our analysis clearly shows that although the use of implicit solvent resulted in too large compactness of monomeric α-Syn, structural properties of monomeric Aß42 and the heterodimer were preserved in explicit-solvent simulations. We anticipate that our study sheds light on the interaction between α-Syn and Aß42 proteins, thus providing the atom-level model required to assess the initial stage of aggregation mechanisms related to Alzheimer's and Parkinson's diseases.

Evaporation Dynamics of Macro- and Nanodroplets on Heated Hydrophilic Rough Substrates: The Effect of Roughness and Scale.

Droplet evaporation on rough substrates plays an essential role in cooling and micro/nanoparticle assembly. Currently, there are numerous macroscopic experiments and theoretical models to investigate the droplet evaporation behavior on rough substrates. However, due to the complexity of this phenomenon, understanding its mechanisms solely through macroscale studies is difficult. To this end, molecular dynamics simulations of the models with distinct roughness factors are performed, and the obtained results are compared with those of relevant experiments of droplet evaporation on three hydrophilic substrates with different roughness average of 0.1, 0.15, and 0.2 µm, respectively. In this way, we assess the evaporation on these rough systems and the effect of scale on macro- and nanodroplets, which allows us to explore deeper the mechanism of droplet evaporation on rough hydrophilic substrates. In particular, we find that in the case of macroscale droplets, the evaporation mode remains the same with increasing roughness, pointing to a combined mixed and constant-contact-radius (CCR) mode. In the case of nanoscale droplets, the evaporation model is the constant-contact-angle mode when the roughness factor r = 1, while the mixed and CCR modes are found for r = 1.5 and 2, respectively. The scale effect has significant influence on the evaporation pattern of droplets on rough hydrophilic substrates. Moreover, it is also found that increasing the roughness of substrates expands the substrate-droplet contact area on both the macro- and nanoscale, which in turn enhances the heat transfer from the substrate toward the droplet. We anticipate that this first systematic analysis of scale effects provides further insights into the evaporation dynamics of droplets on rough hydrophilic substrates and has significant implications for the advancement of nanotechnology.

Ionomer structure and component transport in the cathode catalyst layer of PEM fuel cells: A molecular dynamics study.

The transport of water and protons in the cathode catalyst layer (CCL) of proton exchange membrane (PEM) fuel cells is critical for cell performance, but the underlying mechanism is still unclear. Herein, the ionomer structure and the distribution/transport characteristics of water and protons in CCLs are investigated via all-atom molecular dynamics simulations. The results show that at low water contents, isolated water clusters form in ionomer pores, while proton transport is mainly via the charged sites of the ionomer side chains and the Grotthuss mechanism. Moreover, with increasing water content, water clusters are interconnected to form continuous water channels, which provide effective paths for proton transfer via the vehicular and Grotthuss mechanisms. Increasing the ionomer mass content can enhance the dense arrangement of the ionomer, which, in turn, increases the density of charge sites and improves the proton transport efficiency. When the ionomer mass content is high, the clustering effect reduces the space for water diffusion, increases the proton transport path, and finally decreases the proton transport efficiency. By providing physics insights into the proton transport mechanism, this study is helpful for the structural design and performance improvement of CCLs of PEM fuel cells.

Multiscale simulation of fluids: coupling molecular and continuum.

Computer simulation is an important tool for scientific progress, especially when lab experiments are either extremely costly and difficult or lack the required resolution. However, all of the simulation methods come with limitations. In molecular dynamics (MD) simulation, the length and time scales that can be captured are limited, while computational fluid dynamics (CFD) methods are built on a range of assumptions, from the continuum hypothesis itself, to a variety of closure assumptions. To address these issues, the coupling of different methodologies provides a way to retain the best of both methods. Here, we provide a perspective on multiscale simulation based on the coupling of MD and CFD with each a distinct part of the same simulation domain. This style of coupling allows molecular detail to be present only where it is needed, so CFD can model larger scales than possible with MD alone. We present a unified perspective of the literature, showing the links between the two main types of coupling, state and flux, and discuss the varying assumptions in their use. A unique challenge in such coupled simulation is obtaining averages and constraining local parts of a molecular simulation. We highlight that incorrect localisation has resulted in an error in the literature. We then finish with some applications, focused on the simulation of fluids. Thus, we hope to motivate further research in this exciting area with applications across the spectrum of scientific disciplines.

Molecular dynamics simulation of the coalescence of surfactant-laden droplets.

We investigate the coalescence of surfactant-laden water droplets by using several different surfactant types and a wide range of concentrations by means of a coarse-grained model obtained by the statistical associating fluid theory. Our results demonstrate in detail a universal mass transport mechanism of surfactant across many concentrations and several surfactant types during the process. Coalescence initiation is seen to occur via a single pinch due to aggregation of surface surfactant, and its remnants tend to become engulfed in part inside the forming bridge. Across the board we confirm the existence of an initial thermal regime with constant bridge width followed by a later inertial regime with bridge width scaling roughly as the square root of time, but see no evidence of an intermediate viscous regime. Coalescence becomes slower as surfactant concentration grows, and we see evidence of the appearance of a further slowdown of a different nature for several times the critical concentration. We anticipate that our results provide further insights in the mechanisms of coalescence of surfactant-laden droplets.

Antidurotaxis Droplet Motion onto Gradient Brush Substrates.

Durotaxis motion is a spectacular phenomenon manifesting itself by the autonomous motion of a nano-object between parts of a substrate with different stiffness. This motion usually takes place along a stiffness gradient from softer to stiffer parts of the substrate. Here, we propose a new design of a polymer brush substrate that demonstrates antidurotaxis droplet motion, that is, droplet motion from stiffer to softer parts of the substrate. By carrying out extensive molecular dynamics simulation of a coarse-grained model, we find that antidurotaxis is solely controlled by the gradient in the grafting density of the brush and is favorable for fluids with a strong attraction to the substrate (low surface energy). The driving force of the antidurotaxial motion is the minimization of the droplet-substrate interfacial energy, which is attributed to the penetration of the droplet into the brush. Thus, we anticipate that the proposed substrate design offers a new understanding and possibilities in the area of autonomous motion of droplets for applications in microfluidics, energy conservation, and biology.

Unidirectional Droplet Propulsion onto Gradient Brushes without External Energy Supply.

Using extensive molecular dynamics simulation of a coarse-grained model, we demonstrate the possibility of sustained unidirectional motion (durotaxis) of droplets without external energy supply when placed on a polymer brush substrate with stiffness gradient in a certain direction. The governing key parameters for the specific substrate design studied, which determine the durotaxis efficiency, are found to be the grafting density of the brush and the droplet adhesion to the brush surface, whereas the strength of the stiffness gradient, the viscosity of the droplet, or the length of the polymer chains of the brush have only a minor effect on the process. It is shown that this durotaxial motion is driven by the steady increase of the interfacial energy between droplet and brush as the droplet moves from softer to stiffer parts of the substrate whereby the mean driving force gradually declines with decreasing roughness of the brush surface. We anticipate that our findings indicate further possibilities in the area of nanoscale motion without external energy supply.

Two-dimensional partitioned square ice confined in graphene/graphite nanocapillaries.

As one of the most fascinating confined water/ice phenomena, two-dimensional square ice has been extensively studied and experimentally confirmed in recent years. Apart from the unidirectional homogeneous square icing patterns considered in previous studies, the multidirectional partitioned square icing patterns are discovered in this study and characterized by molecular dynamics (MD) simulations. Square icing parameters are proposed to quantitatively distinguish the partitioned patterns from the homogeneous patterns and the liquid water. The number of graphene monolayers n is varied in this study, and the results show that it is more energetically favorable to form partitioned square icing patterns when the water molecules are confined between graphite sheets (n ≥ 2) compared to graphene (n = 1). This phenomenon is insensitive to n as long as n ≥ 2 because of the short-range nature of the interaction between water molecules and the carbon substrate. Moreover, it is energetically unfavorable to form partitioned square icing patterns for a single layer of water molecules even for n ≥ 2, verifying that the interaction between layers of water molecules is another dominant factor in the formation of partitioned structures. The conversion from partitioned structure to homogeneous square patterns is investigated by changing the pressure and the temperature. Based on the comprehensive MD simulations, this study unveils the formation mechanism of the partitioned square icing patterns.

Off-Lattice Monte-Carlo Approach for Studying Nucleation and Evaporation Phenomena at the Molecular Scale.

Droplet nucleation and evaporation are ubiquitous in nature and many technological applications, such as phase-change cooling and boiling heat transfer. So far, the description of these phenomena at the molecular scale has posed challenges for modelling with most of the models being implemented on a lattice. Here, we propose an off-lattice Monte-Carlo approach combined with a grid that can be used for the investigation of droplet formation and evaporation. We provide the details of the model, its implementation as Python code, and results illustrating its dependence on various parameters. The method can be easily extended for any force-field (e.g., coarse-grained, all-atom models, and external fields, such as gravity and electric field). Thus, we anticipate that the proposed model will offer opportunities for a wide range of studies in various research areas involving droplet formation and evaporation and will also form the basis for further method developments for the molecular modelling of such phenomena.

Droplet Control Based on Pinning and Substrate Wettability.

Pinning of liquid droplets on solid substrates is ubiquitous and plays an essential role in many applications, especially in various areas such as microfluidics and biology. Although pinning can often reduce the efficiency of various applications, a deeper understanding of this phenomenon can actually offer possibilities for technological exploitation. Here, by means of molecular dynamics simulation, we identify the conditions that lead to droplet pinning or depinning and discuss the effects of key parameters in detail, such as the height of the physical pinning barrier and the wettability of the substrates. Moreover, we describe the mechanism of barrier crossing by the droplet upon depinning, identify the driving force of this process, and, also, elucidate the dynamics of the droplet. Not only does our work provide a detailed description of the pinning and depinning processes but also it explicitly highlights how both processes can be exploited in nanotechnology applications to control the droplet motion. Hence, we anticipate that our study will have significant implications for the nanoscale design of substrates in micro- and nanoscale systems and will assist with assessing pinning effects in various applications.

Zinc binding promotes greater hydrophobicity in Alzheimer's Aß42 peptide than copper binding: Molecular dynamics and solvation thermodynamics studies.

The aggregation of Aß42 peptides is considered as one of the main causes for the development of Alzheimer's disease. In this context, Zn2+ and Cu2+ play a significant role in regulating the aggregation mechanism, due to changes in the structural and the solvation free energy of Aß42. In practice, experimental studies are not able to determine the latter properties, since the Aß42-Zn2+ and Aß42-Cu2+ peptide complexes are intrinsically disordered, exhibiting rapid conformational changes in the aqueous environment. Here, we investigate atomic structural variations and the solvation thermodynamics of Aß42, Aß42-Cu2+ , and Aß42-Zn2+ systems in explicit solvent (water) by using quantum chemical structures as templates for a metal binding site and combining extensive all-atom molecular dynamics (MD) simulations with a thorough solvation thermodynamic analysis. Our results show that the zinc and copper coordination results in a significant decrease of the solvation free energy in the C-terminal region (Met35-Val40), which in turn leads to a higher structural disorder. In contrast, the ß-sheet formation at the same C-terminal region indicates a higher solvation free energy in the case of Aß42. The solvation free energy of Aß42 increases upon Zn2+ binding, due to the higher tendency of forming the ß-sheet structure at the Leu17-Ala42 residues, in contrast to the case of binding with Cu2+ . Finally, we find the hydrophobicity of Aß42-Zn2+ in water is greater than in the case of Aß42-Cu2+ .

Fast Estimation of the Blood-Brain Barrier Permeability by Pulling a Ligand through a Lipid Membrane.

The blood-brain barrier (BBB) is a physical barrier that regulates the homeostasis of the neural microenvironment. A relative estimate of the BBB permeability, which is important for drug design, may be experimentally provided by the logBB (the blood-brain concentration ratio) and the logPS (permeability-surface-area product), while many computational methods aim to identify key properties that correlate well with these quantities. Although currently existing computational methods (e.g., quantitative structure activity relation) have made a significant contribution in screening various compounds that could potentially translocate through the BBB, they are unable to provide a physical explanation of the underlying processes and they can often be computationally demanding. Here, we use steered molecular dynamics simulation to estimate the BBB permeability of various compounds on the basis of simple lipid-membrane models by computing the nonequilibrium work, Wneq, produced by pulling the compounds through the membrane. We found that the values of Wneq correlate remarkably well with logBB and logPS for a range of compounds and different membrane types and pulling speeds, independently of the choice of force field. Moreover, our results provide insight into the role of hydrogen bonds, the energetic barriers, and the forces exerted on the ligands during their pulling. Our method is computationally easy to implement and fast. Therefore, we anticipate that it could provide a reliable prescreening tool for estimating the relative permeability of the BBB to various substances.

Ising universality in the two-dimensional Blume-Capel model with quenched random crystal field.

Using high-precision Monte Carlo simulations based on a parallel version of the Wang-Landau algorithm and finite-size scaling techniques, we study the effect of quenched disorder in the crystal-field coupling of the Blume-Capel model on a square lattice. We mainly focus on the part of the phase diagram where the pure model undergoes a continuous transition, known to fall into the universality class of a pure Ising ferromagnet. A dedicated scaling analysis reveals concrete evidence in favor of the strong universality hypothesis with the presence of additional logarithmic corrections in the scaling of the specific heat. Our results are in agreement with an early real-space renormalization-group study of the model as well as a very recent numerical work where quenched randomness was introduced in the energy exchange coupling. Finally, by properly fine tuning the control parameters of the randomness distribution we also qualitatively investigate the part of the phase diagram where the pure model undergoes a first-order phase transition. For this region, preliminary evidence indicate a smoothing of the transition to second-order with the presence of strong scaling corrections.

Mixing-demixing transition in polymer-grafted spherical nanoparticles.

Polymer-grafted nanoparticles (PGNPs) can provide property profiles that cannot be obtained individually by polymers or nanoparticles (NPs). Here, we have studied the mixing-demixing transition of symmetric copolymer melts of polymer-grafted spherical nanoparticles by means of coarse-grained molecular dynamics simulation and a theoretical mean-field model. We find that a larger size of NPs leads to higher stability for a given number of grafted chains and chain lengths, reaching a point where demixing is not possible. Most importantly, the increase in the number of grafted chains, Ng, can initially favour the phase separation of PGNPs, but a further increase can lead to more difficult demixing. The reason is the increasing impact of an effective core that forms as the grafting density of the tethered polymer chains around the NPs increases. The range and exact values of Ng where this change in behaviour takes place depend on the NP size and the chain length of the grafted polymer chains. Our study elucidates the phase behaviour of PGNPs and in particular the influence of the grafting density on the phase behaviour of the systems, anticipating that it will open new doors in the understanding of these systems with implications in materials science and medicine.

Surface nanobubbles: Theory, simulation, and experiment. A review.

Surface nanobubbles (NBs) are stable gaseous phases in liquids that form at the interface with solid substrates. They have been particularly intriguing for their high stability that contradicts theoretical expectations and their potential relevance for many technological applications. Here, we present the current state of the art in this research area by discussing and contrasting main results obtained from theory, simulation and experiment, and presenting their limitations. We also provide future perspectives anticipating that this review will stimulate further studies in the research area of surface NBs.

Mechanical and thermodynamic properties of Aß42, Aß40, and α-synuclein fibrils: a coarse-grained method to complement experimental studies.

We perform molecular dynamics simulation on several relevant biological fibrils associated with neurodegenerative diseases such as Aß40, Aß42, and α-synuclein systems to obtain a molecular understanding and interpretation of nanomechanical characterization experiments. The computational method is versatile and addresses a new subarea within the mechanical characterization of heterogeneous soft materials. We investigate both the elastic and thermodynamic properties of the biological fibrils in order to substantiate experimental nanomechanical characterization techniques that are quickly developing and reaching dynamic imaging with video rate capabilities. The computational method qualitatively reproduces results of experiments with biological fibrils, validating its use in extrapolation to macroscopic material properties. Our computational techniques can be used for the co-design of new experiments aiming to unveil nanomechanical properties of biological fibrils from a point of view of molecular understanding. Our approach allows a comparison of diverse elastic properties based on different deformations , i.e., tensile (Y L), shear (S), and indentation (Y T) deformation. From our analysis, we find a significant elastic anisotropy between axial and transverse directions (i.e., Y T > Y L) for all systems. Interestingly, our results indicate a higher mechanostability of Aß42 fibrils compared to Aß40, suggesting a significant correlation between mechanical stability and aggregation propensity (rate) in amyloid systems. That is, the higher the mechanical stability the faster the fibril formation. Finally, we find that α-synuclein fibrils are thermally less stable than ß-amyloid fibrils. We anticipate that our molecular-level analysis of the mechanical response under different deformation conditions for the range of fibrils considered here will provide significant insights for the experimental observations.

Monte Carlo study of the interfacial adsorption of the Blume-Capel model.

We investigate the scaling of the interfacial adsorption of the two-dimensional Blume-Capel model using Monte Carlo simulations. In particular, we study the finite-size scaling behavior of the interfacial adsorption of the pure model at both its first- and second-order transition regimes, as well as at the vicinity of the tricritical point. Our analysis benefits from the currently existing quite accurate estimates of the relevant (tri)critical-point locations. In all studied cases, the numerical results verify to a level of high accuracy the expected scenarios derived from analytic free-energy scaling arguments. We also investigate the size dependence of the interfacial adsorption under the presence of quenched bond randomness at the originally first-order transition regime (disorder-induced continuous transition) and the relevant self-averaging properties of the system. For this ex-first-order regime, where strong transient effects are shown to be present, our findings support the scenario of a non-divergent scaling, similar to that found in the original second-order transition regime of the pure model.

Generalization of the elastic network model for the study of large conformational changes in biomolecules.

The elastic network (EN) is a prime model that describes the long-time dynamics of biomolecules. However, the use of harmonic potentials renders this model insufficient for studying large conformational changes of proteins (e.g. stretching of proteins, folding and thermal unfolding). Here, we extend the capabilities of the EN model by using a harmonic approximation described by Lennard-Jones (LJ) interactions for far contacts and native contacts obtained from the standard overlap criterion as in the case of Go-like models. While our model is validated against the EN model by reproducing the equilibrium properties for a number of proteins, we also show that the model is suitable for the study of large conformation changes by providing various examples. In particular, this is illustrated on the basis of pulling simulations that predict with high accuracy the experimental data on the rupture force of the studied proteins. Furthermore, in the case of DDFLN4 protein, our pulling simulations highlight the advantages of our model with respect to Go-like approaches, where the latter fail to reproduce previous results obtained by all-atom simulations that predict an additional characteristic peak for this protein. In addition, folding simulations of small peptides yield different folding times for α-helix and ß-hairpin, in agreement with experiment, in this way providing further opportunities for the application of our model in studying large conformational changes of proteins. In contrast to the EN model, our model is suitable for both normal mode analysis and molecular dynamics simulation. We anticipate that the proposed model will find applications in a broad range of problems in biology, including, among others, protein folding and thermal unfolding.

Moving Contact Lines: Linking Molecular Dynamics and Continuum-Scale Modeling.

Despite decades of research, the modeling of moving contact lines has remained a formidable challenge in fluid dynamics whose resolution will impact numerous industrial, biological, and daily life applications. On the one hand, molecular dynamics (MD) simulation has the ability to provide unique insight into the microscopic details that determine the dynamic behavior of the contact line, which is not possible with either continuum-scale simulations or experiments. On the other hand, continuum-based models provide a link to the macroscopic description of the system. In this Feature Article, we explore the complex range of physical factors, including the presence of surfactants, which governs the contact line motion through MD simulations. We also discuss links between continuum- and molecular-scale modeling and highlight the opportunities for future developments in this area.

Stiffness-guided motion of a droplet on a solid substrate.

A range of technologies require the directed motion of nanoscale droplets on solid substrates. A way of realizing this effect is durotaxis, whereby a stiffness gradient of a substrate can induce directional motion without requiring an energy source. Here, we report on the results of extensive molecular dynamics investigations of droplets on a surface with varying stiffness. We find that durotaxis is enhanced by increasing the stiffness gradient and, also, by increased wettability of the substrate, in particular, when the droplet size decreases. We anticipate that our study will provide further insights into the mechanisms of nanoscale directional motion.