Effects of Linking Topology on the Shear Response of Connected Ring Polymers: Catenanes and Bonded Rings Flow Differently.

We perform computer simulations of mechanically linked (poly[2]catenanes, PC) and chemically bonded (bonded rings, BR) pairs of self-avoiding ring polymers in steady shear. We find that BRs develop a novel motif, termed gradient tumbling, rotating around the gradient axis. For the PCs the rings are stretched and display another new pattern, termed slip tumbling. The dynamics of BRs is continuous and oscillatory, whereas that of PCs is intermittent between slip-tumbling attempts. Our findings demonstrate the interplay between topology and hydrodynamics in dilute solutions of connected polymers.

In silico study of the impact of oxidation on pyruvate transmission across the hVDAC1 protein channel.

The overexpression of voltage dependent anion channels (VDACs), particularly VDAC1, in cancer cells compared to normal cells, plays a crucial role in cancer cell metabolism, apoptosis regulation, and energy homeostasis. In this study, we used molecular dynamics (MD) simulations to investigate the effect of a low level of VDAC1 oxidation (induced e.g., by cold atmospheric plasma (CAP)) on the pyruvate (Pyr) uptake by VDAC1. Inhibiting Pyr uptake through VDAC1 can suppress cancer cell proliferation. Our primary target was to study the translocation of Pyr across the native and oxidized forms of hVDAC1, the human VDAC1. Specifically, we employed MD simulations to analyze the hVDAC1 structure by modifying certain cysteine residues to cysteic acids and methionine residues to methionine sulfoxides, which allowed us to investigate the effect of oxidation. Our results showed that the free energy barrier for Pyr translocation through the native and oxidized channel was approximately 4.3 ± 0.7 kJ mol-1 and 10.8 ± 1.8 kJ mol-1, respectively. An increase in barrier results in a decrease in rate of Pyr permeation through the oxidized channel. Thus, our results indicate that low levels of CAP oxidation reduce Pyr translocation, resulting in decreased cancer cell proliferation. Therefore, low levels of oxidation are likely sufficient to treat cancer cells given the inhibition of Pyr uptake.

Reply to the 'Comment on "Effects of topological constraints on linked ring polymers in solvents of varying quality"' by M. Tsige and H. Guo, Soft Matter, 2024, 20, DOI: 10.1039/D3SM01614E.

In the preceding Comment, Drs Tsige and Guo compare their findings about the θ-temperatures of linear chains, ring polymers and poly[n]catenanes with those of previous work by us [Z. A. Dehaghani, I. Chubak, C. N. Likos and M. R. Ejtehadi, Soft Matter, 2020, 16, 3029-3038] and point out that the ordering they obtain for these three quantities is, for large degrees of polymerisation, the reverse of the one we had found in our own investigations. We thank the authors of the Comment for their remarks and we appreciate their detailed investigations, which emphasise the importance of understanding the properties of topological polymers and their behaviour under varying solvent quality. We point out, however, that the discrepancy found by Tsige and Guo is only apparent because it pertains to the Θ-temperature of rings and poly[n]catenanes with the same overall molecular weight, whereas in our work we compared the Θ-temperature of a constituent ring of the poly[n]catenane with that of the entire mechanically linked macromulecule.

Programmable Transport of C60 by Straining Graphene Substrate.

Controlling the maneuverability of nanocars and molecular machines on the surface is essential for the targeted transportation of materials and energy at the nanoscale. Here, we evaluate the motion of fullerene, as the most popular candidate for use as a nanocar wheel, on the graphene nanoribbons with strain gradients based on molecular dynamics (MD), and theoretical approaches. The strain of the examined substrates linearly decreases by 20%, 16%, 12%, 8%, 4%, and 2%. MD calculations were performed with the open source LAMMPS solver. The essential physics of the interactions is captured by Lennard-Jones and Tersoff potentials. The motion of C60 on the graphene nanoribbon is simulated in canonical ensemble, which is implanted by using a Nose-Hoover thermostat. Since the potential energy of C60 is lower on the unstrained end of nanoribbons, this region is energetically more favorable for the molecule. As the strain gradient of the surface increases, the trajectories of the motion and the C60 velocity indicate more directed movements along the gradient of strain on the substrate. Based on the theoretical relations, it was shown that the driving force and diffusion coefficient of the C60 motion respectively find linear and quadratic growth with the increase of strain gradient, which is confirmed by MD simulations. To understand the effect of temperature, at each strain gradient of substrate, the simulations are repeated at the temperatures of 100, 200, 300, and 400 K. The large ratio of longitudinal speed to the transverse speed of fullerene at 100 and 200 K refers to the rectilinear motion of molecule at low temperatures. Using successive strain gradients on the graphene in perpendicular directions, we steered the motion of C60 to the desired target locations. The programmable transportation of nanomaterials on the surface has a significant role in different processes at the nanoscale, such as bottom-up assembly.

Counterintuitive properties of evolutionary measures: A stochastic process study in cyclic population structures with periodic environments.

Local environmental interactions are a major factor in determining the success of a new mutant in structured populations. Spatial variations in the concentration of genotype-specific resources change the fitness of competing strategies locally and thus can drastically change the outcome of evolutionary processes in unintuitive ways. The question is how such local environmental variations in network population structures change the condition for selection and fixation probability of an advantageous (or deleterious) mutant. We consider linear graph structures and focus on the case where resources have a spatial periodic pattern. This is the simplest model with two parameters, length scale and fitness scales, representing heterogeneity. We calculate fixation probability and fixation times for a constant population birth-death process as fitness heterogeneity and period vary. Fixation probability is affected by not only the level of fitness heterogeneity but also spatial scale of resources variations set by period of distribution T. We identify conditions for which a previously a deleterious mutant (in a uniform environment) becomes beneficial as fitness heterogeneity is increased. We observe cases where the fixation probability of both mutant and resident types are more than their neutral value, 1/N, simultaneously. This coincides with exponential increase in time to fixation which points to potential coexistence of resident and mutant types. Finally, we discuss the effect of the 'fitness shift' where the fitness function of two types has a phase difference. We observe significant increases (or decreases) in the fixation probability of the mutant as a result of such phase shift.

Effect of Cysteine Oxidation in SARS-CoV-2 Receptor-Binding Domain on Its Interaction with Two Cell Receptors: Insights from Atomistic Simulations.

Binding of the SARS-CoV-2 S-glycoprotein to cell receptors is vital for the entry of the virus into cells and subsequent infection. ACE2 is the main cell receptor for SARS-CoV-2, which can attach to the C-terminal receptor-binding domain (RBD) of the SARS-CoV-2 S-glycoprotein. The GRP78 receptor plays an anchoring role, which attaches to the RBD and increases the chance of other RBDs binding to ACE2. Although high levels of reactive oxygen and nitrogen species (RONS) are produced during viral infections, it is not clear how they affect the RBD structure and its binding to ACE2 and GRP78. In this research, we apply molecular dynamics simulations to study the effect of oxidation of the highly reactive cysteine (Cys) amino acids of the RBD on its binding to ACE2 and GRP78. The interaction energy of both ACE2 and GRP78 with the whole RBD, as well as with the RBD main regions, is compared in both the native and oxidized RBDs. Our results show that the interaction energy between the oxidized RBD and ACE2 is strengthened by 155 kJ/mol, increasing the binding of the RBD to ACE2 after oxidation. In addition, the interaction energy between the RBD and GRP78 is slightly increased by 8 kJ/mol after oxidation, but this difference is not significant. Overall, these findings highlight the role of RONS in the binding of the SARS-CoV-2 S-glycoprotein to host cell receptors and suggest an alternative mechanism by which RONS could modulate the entrance of viral particles into the cells.

Electronic polarization effects on membrane translocation of anti-cancer drugs.

Free-energy calculations are crucial for investigating biomolecular interactions. However, in theoretical studies, the neglect of electronic polarization can reduce predictive capabilities, specifically for free-energy calculations. To effectively mimick polarization, we explore a Charge Switching (CS) model, aiming to narrow the gap between computational and experimental results. The model requires quantum-level partial charge calculations of the molecule in different environments, combined with atomistic MD simulations. Studying three different anti-cancer drug molecules with three different phospholipid membranes, we show that the method significantly improves agreement with available experimental data. In contrast, using conventional fixed charge atomistic methods, qualitative discrepancies with experiments are observed, and we show that neglecting polarization may lead to an unphysical free energy sign inversion. While the CS method is here applied to anti-cancer drug-membrane translocation, it could be used more generally to study processes considering solvent effects.

Collective movement and thermal stability of fullerene clusters on the graphene layer.

Understanding the motion characteristics of fullerene clusters on the graphene surface is critical for designing surface manipulation systems. Toward this purpose, using the molecular dynamics method, we evaluated six clusters of fullerenes including 1, 2, 3, 5, 10, and 25 molecules on the graphene surface, in the temperature range of 25 to 500 K. First, the surface motion of clusters is studied at 200 K and lower temperatures, in which fullerenes remain as a single group. The trajectories of the motion as well as the diffusion coefficients indicate the reduction of surface mobility as a response to the increase of the fullerene number. The clusters show normal diffusion at the temperature of 25 K, while they follow the super-diffusion regime at higher temperatures. The separation of fullerenes occurs at 300 K and higher temperatures. Due to the increase of vdW attraction with the increase of the fullerene number, the separation of fullerenes in larger clusters occurs at higher temperatures. The thermal energy at 500 K is sufficient to divide the large C60 clusters into smaller clusters. This energy level is related to the saturation of the interaction energy experienced by individual fullerenes, which can be estimated from the potential energy analysis. The results of simulations reveal that the separation occurs at the edge of clusters. Moreover, we studied the thermal stability of multilayer fullerene clusters on graphene. The simulation results indicate the tendency of multilayer clusters to locate on the surface, which implies the wetting property of C60s on the graphene layer.

Nanocar swarm movement on graphene surfaces.

Investigation of nanomachine swarm motion is useful in the design of molecular transportation systems as well as in understanding the assembly process on the surface. Here, we evaluate the motion of the clusters of nanocars on graphene surfaces, using molecular dynamics (MD) simulations. The mechanism of motion of single nanocars is evaluated by considering the rotation of the wheels, direction of the nanocars' speed and comparing the characteristics of the surface motion of nanocars and similar absorbed molecules. The mentioned analyses reveal that, in the thermally activated surface motion of the nanocars, sliding movements are the dominant mode of motion. A coarse grained (CG) model is proposed for some preliminary studies such as finding the stable orientation of two nanocars. The established model indicates three stable orientations for a pair of nanocars, which are verified by MD simulations and the analysis of potential energy. The radius of gyration and the root mean square deviation (RMSD) are employed to evaluate the configuration of larger nanocar clusters. Nanocar clusters change their configuration at 300 K and higher temperatures; however, there is a threshold temperature (600 K) at which different clusters are broken because at this temperature the thermal fluctuation energy dominates the vdW attraction between a nanocar in the perimeter and the other nanocars of the cluster. The surface motions of the nanocar clusters are investigated at temperatures at which the clusters are thermally stable by computing different motion parameters such as mean square displacements (MSDs), diffusion coefficients and anomaly parameters. As the population of clusters increases from 1 to 10 nanocars, the motion regime changes from long-range to small-range displacements which is attributed to the energy wasted by intermolecular vdW interactions. The anomaly parameters of the motions reveal that the clusters experience almost normal diffusion at low temperatures, while they find a super-diffusive regime at higher temperatures. Ultimately, the preferred arrangement of nanocar assembly can be utilized to fabricate special nanostructures on the surface including molecular rings and chains.

A modified Jarzynski free-energy estimator to eliminate non-conservative forces and its application in nanoparticle-membrane interactions.

Computational methods to understand interactions in bio-complex systems are however limited to time-scales typically much shorter than in Nature. For example, on the nanoscale level, interactions between nanoparticles (NPs)/molecules/peptides and membranes are central in complex biomolecular processes such as membrane-coated NPs or cellular uptake. This can be remedied by the application of e.g. Jarzynski's equality where thermodynamic properties are extracted from non-equilibrium simulations. Although, the out of equilibrium work leads to non-conservative forces. We here propose a correction Pair Forces method, that removes these forces. Our proposed method is based on the calculation of pulling forces in backward and forward directions for the Jarzynski free-energy estimator using steered molecular dynamics simulation. Our results show that this leads to much improvement for NP-membrane translocation free energies. Although here we have demonstrated the application of the method in molecular dynamics simulation, it could be applied for experimental approaches.

Effects of topological constraints on linked ring polymers in solvents of varying quality.

We investigate the effects of topological constraints in catenanes composed of interlinked ring polymers on their size in a good solvent as well as on the location of their θ-point when the solvent quality is worsened. We mainly focus on poly[n]catenanes consisting of n ring polymers each of length m interlocked in a linear fashion. Using molecular dynamics simulations, we study the scaling of the poly[n]catenane's radius of gyration in a good solvent, assuming in general that Rg∼mµnν and we find that µ = 0.65 ± 0.02 and ν = 0.60 ± 0.01 for the range of n and m considered. These findings are further rationalized with the help of a mean-field Flory-like theory yielding the values of µ = 16/25 and ν = 3/5, consistent with the numerical results. We show that individual rings within catenanes feature a surplus swelling due to the presence of NL topological links. Furthermore, we consider poly[n]catenanes in solvents of varying quality and we demonstrate that the presence of topological links leads to an increase of its θ-temperature in comparison to isolated linear and ring chains with the following ordering: T > T > T. Finally, we show that the presence of links similarly raises the θ-temperature of a single linked ring in comparison to an unlinked one, bringing its θ-temperature close to the one of a poly[n]catenane.

GAG positioning on IL-1RI; A mechanism regulated by dual effect of glycosylation.

IL-1RI is the signaling receptor for the IL-1 family of cytokines that are involved in establishment of the innate and acquired immune systems. Glycosylated extracellular (EC) domain of the IL-1RI binds to agonist such as IL-1ß or antagonist ligands and the accessory protein to form the functional signaling complex. Dynamics and ligand binding of the IL-1RI is influenced by presence of the glycosaminoglycans (GAGs) of the EC matrix. Here a combination of molecular dockings and molecular dynamics simulations of the unglycosylated, partially N-glycosylated and fully N-glycosylated IL-1RI EC domain in the apo, GAG-bound and IL-1ß-bound states were carried out to explain the co-occurring dynamical effect of receptor's glycosylation and GAGs. It was shown that the IL-1RI adopts two types of "extended" and "locked" conformations in its dynamical pattern, and glycosylation maintains the receptor in the latter form. Maintaining the receptor in the locked conformation disfavors IL-1ß binding by burying its two binding site on the IL-1RI EC domain. Glycosylation disfavors GAG binding to the extended IL-1RI EC domain by sterically limiting the GAGs degrees of freedom in targeting its binding site, while it favors GAG binding to the locked IL-1RI by favorable packing interactions.

Topology of internally constrained polymer chains.

Linear chains with intra-chain contacts can adopt different topologies and allow transitions between them, but it remains unclear how this process can be controlled. This question is important to systems ranging from proteins to chromosomes, which can adopt different conformations that are key to their function and toxicity. Here, we investigate how the topological dynamics of a simple linear chain is affected by interactions with a binding partner, using Monte Carlo and Molecular Dynamics simulations. We show that two point contacts with a binding partner are sufficient to accelerate or decelerate the formation of particular topologies within linear chains. Computed ''folding-time landscapes" that detail the folding time within the topology space show that such contacts deform these landscapes and hence alter the occupation probability of topological states. The results provide a mechanism by which chain topologies can be controlled externally, which opens up the possibility of regulating topological dynamics and the formation of more complex topologies. The findings may have important implications for understanding the mechanism of chaperone action as well as genome architecture and evolution.

Nanomechanical properties of lipid bilayer: asymmetric modulation of lateral pressure and surface tension due to protein insertion in one leaflet of a bilayer.

The lipid membranes of living cells form an integral part of biological systems, and the mechanical properties of these membranes play an important role in biophysical investigations. One interesting problem to be evaluated is the effect of protein insertion in one leaflet of a bilayer on the physical properties of lipid membrane. In the present study, an all atom (fine-grained) molecular dynamics simulation is used to investigate the binding of cytotoxin A3 (CTX A3), a cytotoxin from snake venom, to a phosphatidylcholine lipid bilayer. Then, a 5-microsecond [corrected] coarse-grained molecular dynamics simulation is carried out to compute the pressure tensor, lateral pressure, surface tension, and first moment of lateral pressure in each monolayer. Our simulations reveal that the insertion of CTX A3 into one monolayer results in an asymmetrical change in the lateral pressure and corresponding spatial distribution of surface tension of the individual bilayer leaflets. The relative variation in the surface tension of the two monolayers as a result of a change in the contribution of the various intermolecular forces may potentially be expressed morphologically.

Dynamics of fluid bilayer vesicles: Soft meshes and robust curvature energy discretization.

Continuum models like the Helfrich Hamiltonian are widely used to describe fluid bilayer vesicles. Here we study the molecular dynamics compatible dynamics of the vertices of two-dimensional meshes representing the bilayer, whose in-plane motion is only weakly constrained. We show (i) that Jülicher's discretization of the curvature energy offers vastly superior robustness for soft meshes compared to the commonly employed expression by Gommper and Kroll and (ii) that for sufficiently soft meshes, the typical behavior of fluid bilayer vesicles can emerge even if the mesh connectivity remains fixed throughout the simulations. In particular, soft meshes can accommodate large shape transformations, and the model can generate the typical ℓ^{-4} signal for the amplitude of surface undulation modes of nearly spherical vesicles all the way up to the longest wavelength modes. Furthermore, we compare results for Newtonian, Langevin, and Brownian dynamics simulations of the mesh vertices to demonstrate that the internal friction of the membrane model is negligible, making it suitable for studying the internal dynamics of vesicles via coupling to hydrodynamic solvers or particle-based solvent models.

Electrochromic Sensor Augmented with Machine Learning for Enzyme-Free Analysis of Antioxidants.

Our study presents an electrochromic sensor that operates without the need for enzymes or multiple oxidant reagents. This sensor is augmented with machine learning algorithms, enabling the identification, classification, and prediction of six different antioxidants with high accuracy. We utilized polyaniline (PANI), Prussian blue (PB), and copper-Prussian blue analogues (Cu-PBA) at their respective oxidation states as electrochromic materials (ECMs). By designing three readout channels with these materials, we were able to achieve visual detection of antioxidants without relying on traditional "lock and key" specific interactions. Our sensing approach is based on the direct electrochemical reactions between oxidized electrochromic materials (ECMsox) as electron acceptors and various antioxidants, which act as electron donors. This interaction generates unique fingerprint patterns by switching the ECMsox to reduced electrochromic materials (ECMsred), causing their colors to change. Through the application of density functional theory (DFT), we demonstrated the molecular-level basis for the distinct multicolor patterns. Additionally, machine learning algorithms were employed to correlate the optical patterns with RGB data, enabling complex data analysis and the prediction of unknown samples. To demonstrate the practical applications of our design, we successfully used the EC sensor to diagnose antioxidants in serum samples, indicating its potential for the on-site monitoring of antioxidant-related diseases. This advancement holds promise for various applications, including the real-time monitoring of antioxidant levels in biological samples, the early diagnosis of antioxidant-related diseases, and personalized medicine. Furthermore, the success of our electrochromic sensor design highlights the potential for exploring similar strategies in the development of sensors for diverse analytes, showcasing the versatility and adaptability of this approach.

Glycan-mediated functional assembly of IL-1RI: structural insights into completion of the current description for immune response.

Interleukin 1 Receptor type I (IL-1RI) is a multi-domain transmembrane receptor that triggers the inflammatory response. Understanding its detailed mechanism of action is crucial for treating immune disorders. IL-1RI is activated upon formation of its functional assembly that occurs by binding of the IL-1 cytokine and the accessory protein (Il-1RAcP) to it. X-ray crystallography, small-Angle X-ray Scattering and molecular dynamics simulation studies showed that IL-1RI adopts two types of 'compact' and 'extended' conformational states in its dynamical pattern. Furthermore, glycosylation has shown to play a critical role in its activation process. Here, classical and accelerated atomistic molecular dynamics were carried out to examine the role of full glycosylation of IL-1RI and IL-1RAcP in arrangement of the functional assembly. Simulations showed that the 'compact' and 'extended' IL-1RI form two types of 'cytokine-inaccessible-non-signaling' and 'cytokine-accessible-signaling' assemblies with the IL-1RacP, respectively that are both abiding in the presence of glycans. Suggesting that the cytokine binding to IL-1RI is not required for the formation of IL-1RI-IL-1RAcP complex and the 'compact' complex could act as a down-regulatory mechanism. The 'extended' complex is maintained by formation of several persistent hydrogen bonds between the IL-1RI-IL-1RAcP inter-connected glycans. Taken together, it was shown that full glycosylation regulates formation of the IL-1RI functional assembly and play critical role in cytokine biding and triggering the IL-1RI involved downstream pathways in the cell.Communicated by Ramaswamy H. Sarma.

Conformation- and phosphorylation-dependent electron tunnelling across self-assembled monolayers of tau peptides.

We report on charge transport across self-assembled monolayers (SAMs) of short tau peptides by probing the electron tunneling rates and quantum mechanical simulation. We measured the electron tunneling rates across SAMs of carboxyl-terminated linker molecules (C6H12O2S) and short cis-tau (CT) and trans-tau (TT) peptides, supported on template-stripped gold (AuTS) bottom electrode, with Eutectic Gallium-Indium (EGaIn)(EGaIn) top electrode. Measurements of the current density across thousands of AuTS/linker/tau//Ga2O3/EGaIn single-molecule junctions show that the tunneling current across CT peptide is one order of magnitude lower than that of TT peptide. Quantum mechanical simulation demonstrated a wider energy bandgap of the CT peptide, as compared to the TT peptide, which causes a reduction in its electron tunneling current. Our findings also revealed the critical role of phosphorylation in altering the charge transport characteristics of short peptides; more specifically, we found that the presence of phosphate groups can reduce the energy band gap in tau peptides and alter their electrical properties. Our results suggest that conformational and phosphorylation of short peptides (e.g., tau) can significantly change their charge transport characteristics and energy levels.

First passage time distribution of chaperone driven polymer translocation through a nanopore: homopolymer and heteropolymer cases.

Combining the advection-diffusion equation approach with Monte Carlo simulations we study chaperone driven polymer translocation of a stiff polymer through a nanopore. We demonstrate that the probability density function of first passage times across the pore depends solely on the Péclet number, a dimensionless parameter comparing drift strength and diffusivity. Moreover it is shown that the characteristic exponent in the power-law dependence of the translocation time on the chain length, a function of the chaperone-polymer binding energy, the chaperone concentration, and the chain length, is also effectively determined by the Péclet number. We investigate the effect of the chaperone size on the translocation process. In particular, for large chaperone size, the translocation progress and the mean waiting time as function of the reaction coordinate exhibit pronounced sawtooth-shapes. The effects of a heterogeneous polymer sequence on the translocation dynamics is studied in terms of the translocation velocity, the probability distribution for the translocation progress, and the monomer waiting times.

Impact of temporal correlations on high risk outbreaks of independent and cooperative SIR dynamics.

We first propose a quantitative approach to detect high risk outbreaks of independent and coinfective SIR dynamics on three empirical networks: a school, a conference and a hospital contact network. This measurement is based on the k-means clustering method and identifies proper samples for calculating the mean outbreak size and the outbreak probability. Then we systematically study the impact of different temporal correlations on high risk outbreaks over the original and differently shuffled counterparts of each network. We observe that, on the one hand, in the coinfection process, randomization of the sequence of the events increases the mean outbreak size of high-risk cases. On the other hand, these correlations do not have a consistent effect on the independent infection dynamics, and can either decrease or increase this mean. Randomization of the daily pattern correlations has no strong impact on the size of the outbreak in either the coinfection or the independent spreading cases. We also observe that an increase in the mean outbreak size does not always coincide with an increase in the outbreak probability; therefore, we argue that merely considering the mean outbreak size of all realizations may lead us into falsely estimating the outbreak risks. Our results suggest that some sort of contact randomization in the organizational level in schools, events or hospitals might help to suppress the spreading dynamics while the risk of an outbreak is high.