Full Atomistic Molecular Dynamics Research Articles

Investigation of thermomechanical behaviors of acrylate-based shape memory polymers by molecular dynamics simulation

Shape memory polymers (SMPs) have received a lot of attention lately due to their potential use as actuators in various applications, including robotics and biomedical device. SMPs are a better choice than other smart materials due to their remarkable ability to recover from significant deformations and their ability to be stimulated remotely. Here, we investigate the mechanical and recovery behaviors of SMPs composed of acrylate-based monomers and crosslinkers with varying crosslink densities, using full-atomistic molecular dynamics (MD) simulations. Physical parameters, such as density and glass transition temperature, are determined for systems with different crosslinking densities. Tensile loading is applied to characterize the mechanical characteristics and shape memory behaviors. Furthermore, the shape-memory behavior of the system with highest crosslinking density is investigated to understand the effects of recovery temperature and deformation temperature on shape recovery. Our findings shed light on the critical structural elements that determine shape recovery ability, giving insights for advanced SMP material design and development. This study adds to our fundamental understanding of SMP behavior and has ramifications for a wide range of technological applications.

Interactions of a Novel Anthracycline with Oligonucleotide DNA and Cyclodextrins in an Aqueous Environment.

Berubicin, a chemotherapy medication belonging to the class of anthracyclines, is simulated in double-stranded DNA sequences and cyclodextrins in an aqueous environment via full-atom molecular dynamics simulations on the time scale of microseconds. The drug is studied in both the neutral and protonated states so as to better comprehend the role of its charge in the formed complexes. The noncovalent berubicin-DNA and berubicin-cyclodextrin complexes are investigated in detail, paying special attention to their thermodynamic description by employing the double decoupling method, the solvent balance method, the weighted solvent accessible surface model, and the linear interaction energy method. A novel approach for extracting the desolvation thermodynamics of the binding process is also presented. Both the binding and desolvation Gibbs energies are decomposed into entropic and enthalpic contributions so as to elucidate the nature of complexation and its driving forces. Selected structural and geometrical properties of all the complexes, which are all stable, are analyzed. Both cyclodextrins under consideration are widely utilized for drug delivery purposes, and a comparative investigation between their bound states with berubicin is carried out.

Atomistic mechanism of coupling between cytosolic sensor domain and selectivity filter in TREK K2P channels

The two-pore domain potassium (K2P) channels TREK-1 and TREK-2 link neuronal excitability to a variety of stimuli including mechanical force, lipids, temperature and phosphorylation. This regulation involves the C-terminus as a polymodal stimulus sensor and the selectivity filter (SF) as channel gate. Using crystallographic up- and down-state structures of TREK-2 as a template for full atomistic molecular dynamics (MD) simulations, we reveal that the SF in down-state undergoes inactivation via conformational changes, while the up-state structure maintains a stable and conductive SF. This suggests an atomistic mechanism for the low channel activity previously assigned to the down state, but not evident from the crystal structure. Furthermore, experimentally by using (de-)phosphorylation mimics and chemically attaching lipid tethers to the proximal C-terminus (pCt), we confirm the hypothesis that moving the pCt towards the membrane induces the up-state. Based on MD simulations, we propose two gating pathways by which movement of the pCt controls the stability (i.e., conductivity) of the filter gate. Together, these findings provide atomistic insights into the SF gating mechanism and the physiological regulation of TREK channels by phosphorylation.

K+-Driven Cl-/HCO3- Exchange Mediated by Slc4a8 and Slc4a10.

Slc4a genes encode various types of transporters, including Na+-HCO3- cotransporters, Cl-/HCO3- exchangers, or Na+-driven Cl-/HCO3- exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl-/HCO3- exchanger, which can be driven by either Na+ or K+, prompting investigation into whether other Slc4a members facilitate cation-dependent anion transport. In the present study, we show that either Na+ or K+ drive Cl-/HCO3- exchanger activity in cells overexpressing Slc4a8 or Slc4a10. Further characterization of cation-driven Cl-/HCO3- exchange demonstrated that Slc4a8 and Slc4a10 also mediate Cl- and HCO3--dependent K+ transport. Full-atom molecular dynamics simulation on the recently solved structure of Slc4a8 supports the coordination of K+ at the Na+ binding site in S1. Sequence analysis shows that the critical residues coordinating monovalent cations are conserved among mouse Slc4a8 and Slc4a10 proteins. Together, our results suggest that Slc4a8 and Slc4a10 might transport K+ in the same direction as HCO3- ions in a similar fashion to that described for Na+ transport in the rat Slc4a8 structure.

Two-Stage Dynamic Transformation from δ- to α-CsPbI3.

The phase transformation from δ- to α-CsPbI3has garnered extensive research interest. However, detailed understanding of this structural transformation at atomistic scale remains elusive. Here, we reported the full atomistic molecular dynamics simulation of this important phase transformation using an enhanced sampling method, Metadynamics (MetaD). Particularly, two-stage of dynamic transformation related to [PbI3]- chains' motions was observed, namely, the intrachain rearrangement followed by interchain connection. Moreover, the dynamic motion of Cs+ cations plays an important role in facilitating the interchain connection kinetically. The insights reported in this work will provide valuable guidance for further advancing the understanding of phase transformation of CsPbI3.

Computational evidences of a misfolding event in an aggregation-prone light chain preceding the formation of the non-native pathogenic dimer.

Antibody light chain amyloidosis is a disorder in which protein aggregates, mainly composed of immunoglobulin light chains, deposit in diverse tissues impairing the correct functioning of organs. Interestingly, due to the high susceptibility of antibodies to mutations, AL amyloidosis appears to be strongly patient-specific. Indeed, every patient will display their own mutations that will make the proteins involved prone to aggregation thus hindering the study of this disease on a wide scale. In this framework, determining the molecular mechanisms that drive the aggregation could pave the way to the development of patient-specific therapeutics. Here, we focus on a particular patient-derived light chain, which has been experimentally characterized. We investigated the early phases of the aggregation pathway through extensive full-atom molecular dynamics simulations, highlighting a structural rearrangement and the exposure of two hydrophobic regions in the aggregation-prone species. Next, we moved to consider the pathological dimerization process through docking and molecular dynamics simulations, proposing a dimeric structure as a candidate pathological first assembly. Overall, our results shed light on the first phases of the aggregation pathway for a light chain at an atomic level detail, offering new structural insights into the corresponding aggregation process.

Integration of Lipid-Functionalized Epigallocatechin-3-gallate into PLGA Matrix as a Novel Polyphenol-Based Nanoantioxidant.

The search for polyphenol-based materials with antioxidant activity is a growing research area in the biomedical field. To obtain an efficient and stable nanoantioxidant, a novel biosystem was designed by integrating a lipophilic derivative of epigallocatechin-3-gallate (named EGCG-C18) on the surface of poly(lactic-co-glycolic acid) (PLGA). Poly(vinyl alcohol) (PVA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG2000) were selected as polymeric and lipidic stabilizers, respectively, and their influence on both physical properties and the antioxidant activity of nanoantioxidant was investigated by a combined in silico and experimental approach. Full-atom molecular dynamics (MD) simulations were carried out to describe the different self-assembly processes of all components and the interactions that guided the EGCG-C18 insertion inside the PLGA matrix. Together with infrared spectroscopy results, the formation of an antioxidant lipid shell on the PLGA surface was clear. Dynamic light scattering and transmission electron microscopy showed that in the presence of DSPE-PEG2000, NPs were smaller than those treated with PVA. In addition, the different stabilizers used strongly influenced the ROS-scavenging ability of nanomaterials and this effect was strictly related to the molecular organization of EGCG-C18. MD showed that the apolar interaction between the alkyl chains of DSPE-PEG2000 and EGCG-C18 oriented the phenolic groups of the polyphenol toward the solvent, providing an ability of NP to scavenge hydroxyl radicals over to free EGCG-C18 and PLGA/PVA NPs. Finally, the ability of nanoantioxidants to protect human dermal fibroblasts from cell death induced by oxidative stress has been tested, revealing the high potential of these novel NPs as polyphenol-based materials.

Construction of full-atomistic polymer amorphous structures using reverse-mapping from Kremer-Grest models.

We propose a method to build full-atomistic (FA) amorphous polymer structures using reverse-mapping from coarse-grained (CG) models. In this method, three models with different resolutions are utilized, namely the CG1, CG2, and FA models. It is assumed that the CG1 model is more abstract than the CG2 model. The CG1 is utilized to equilibrate the system, and then sequential reverse-mapping procedures from the CG1 to the CG2 models and from the CG2 to the FA models are conducted. A mapping relation between the CG1 and the FA models is necessary to generate a polymer structure with a given density and radius of chains. Actually, we have used the Kremer-Grest (KG) model as the CG1 and the monomer-level CG model as the CG2 model. Utilizing the mapping relation, we have developed a scheme that constructs an FA polymer model from the KG model. In the scheme, the KG model, the monomer level CG model, and the FA model are successively constructed. The scheme is applied to polyethylene (PE), cis 1,4-polybutadiene (PB), and poly(methyl methacrylate) (PMMA). As a validation, the structures of PE and PB constructed by the scheme were carefully checked through comparison with those obtained using long-time FA molecular dynamics (MD) simulations. We found that both short- and long-range chain structures constructed by the scheme reproduced those obtained by the FA MD simulations. Then, as an interesting application, the scheme is applied to generate an entangled PMMA structure. The results showed that the scheme provides an efficient and easy way to construct amorphous structures of FA polymers.

Molecular dynamics simulation of poly-m-phenylene isophthalamide polymer membrane modified by UiO-66 (NH2) MOF for separation of toluene/methanol mixture

Pervaporation is the purification technology which utilizes the transport properties of polymer membranes and has several important properties: energy efficiency, environmental friendliness, and a high degree of purification. To improve the transport properties, polymer membranes are modified with special nanoparticles. In this work we study the translational mobility of methanol and toluene molecules inside a poly-m-phenylene isophthalamide membrane with and without the nanoparticle of UiO-66 (NH2) metal-organic framework (UiO-66 (NH2) MOF) using full atomistic molecular dynamics simulation with microsecond trajectories. It was found that methanol has a high translational mobility inside the polymer matrix. Moreover, this mobility is significantly increased by addition of UiO-66 (NH2) MOF. Toluene molecules are practically immobile inside the polymer matrix and tend to form clusters with each other. Due to the inclusion of a nanoparticle, toluene molecules “get stuck” inside UiO-66 (NH2) MOF and its surface. We believe that the obtained results will contribute to the purposeful development and study of polymer matrices for the pervaporation process.

Dynamic microstructure evolution of charged kaolinites with counterions during hydration—A large-scale molecular dynamics study

As porous materials, clayey soils are very prone to lose strength under wetting, which may trigger catastrophic engineering accidents or natural disasters. However, the underlying triggering mechanism of pore water fluids at microscale remains unknown due to limited experimental techniques. In the present work, the dynamic hydration process of charged kaolinites with counterions has been fully explored by applying large-scale full-atomistic molecular dynamics. Topology study showed that the dry kaolinites hydrated immediately when exposed to water. Under the control of the ionic hydration effect, the ionic bridging effect, the water bridging effect and the surface adsorption effect, the adsorption behavior of interparticle water molecules experienced instantaneous adsorption, rapid adsorption and expulsion to reach dynamic equilibrium. The interparticle pore water pressure underwent rapid growth, slow growth and exponential growth along with the adsorption of water molecules. After fully hydration, the net distance between two kaolinite particles decreased by 1/5–2/5 with two or three layers of water molecules occupying the interparticle space. The reported results enhanced the comprehension of the dynamic microstructure evolution of kaolinite clay during hydration, which could further sketch interesting scientific avenues for future researches.

Human Glucosylceramide Synthase at Work as Provided by "In Silico" Molecular Docking, Molecular Dynamics, and Metadynamics.

Glucosylceramide synthase (GCS) is an enzyme that catalyzes the first reaction of ceramide glycosylation in sphingolipid metabolism. It represents a primary target in the pharmacological treatment of some lysosomal storage diseases (LSDs), such as Gaucher and Niemann-Pick syndromes. In this study, starting from the model reported in the AlphaFold Protein Structure Database, the location and conformations of GCS substrates and cofactors have been provided by a step-by-step in silico procedure, by which the functional manganese ion and the substrates have been inserted in the GCS structure through combined molecular docking and full-atomistic molecular dynamics approaches, including metadynamics. A detailed analysis by structural dynamics of the complete model system, i.e., the enzyme anchored to the plasma membrane, containing the manganese ion and the two substrates, has been carried out to identify its complex conformational landscape by means of well-tempered metadynamics. A final structure was selected, in which both substrates were present in the active site of the enzyme at minimum distance, thus giving support to a SNi-type reaction mechanism for catalysis. Asp236, Glu235, and Asp144 are found to interact with the metal cofactor, which is able to trap the phosphates of UDP-glucose, while Gly210, Trp276, and Val208 cooperate to provide its correct orientation. Phe205, Cys207, Tyr237, and Leu284 form a pocket for the polar head of the ceramide, which is transiently placed in position to determine the catalytic event, when His193 interacts with the head of the ceramide, thus anchoring the substrate to the active site.

On the Sensitivity and Affinity of Gold, Silver, and Platinum Surfaces against the SARS-CoV-2 Virus: A Comparative Computational Study.

The novel coronavirus disease and its complications have motivated the design of new sensors with the highest sensitivity, and affinity for the detection of the SARS-CoV-2 virus is considered in many research studies. In this research article, we employ full atomistic molecular dynamics (MD) models to study the interactions between the receptor binding domain (RBD) and spike protein of the coronavirus and different metals such as gold (Au), platinum (Pt), and silver (Ag) to analyze their sensitivity against this virus. The comparison between the RBD interactions with ACE2 (angiotensin-converting enzyme 2) and different metals indicates that metals have remarkable effects on the structural features and dynamical properties of the RBD. The binding site of the RBD has more affinity to the surfaces of gold, platinum, and silver than to the other parts of the protein. Moreover, the initial configuration of the RBD relative to the metal surface plays an important role in the stability of metal complexes with the RBD. The binding face of the protein to the metal surface has been changed in the presence of different metals. In other words, the residues of the RBD that participate in RBD interactions with the metals are different irrespective of the initial configurations in which the [Asn, Thr, Tyr], [Ser, Thr, Tyr], and [Asn, Asp, Tyr] residues of the protein have a greater affinity to Ag, Au, and Pt, respectively. The corresponding metals have a considerable affinity to the RBD, which due to strong interactions with the protein can change the secondary structure and structural features. Based on the obtained results during the complexation process between the protein and metals, the helical structure of the protein changes to the bend and antiparallel β-sheets. The calculated binding energies for the RBD complexes with silver, gold, and platinum are -95.03, -138.03, and -133.96 kcal·mol-1, respectively. The adsorption process of the spike protein on the surfaces of different metals represents similar results and indicates that the entire spike protein of the coronavirus forms a more stable complex with the gold surface compared with other metals. Moreover, the RBD of the spike protein has more interactions with the surfaces than with the other parts of the protein. Therefore, it is possible to predict the properties of the coronavirus on the metal surface based on the dynamical behavior of the RBD. Overall, our computational results confirm that the gold surface can be considered as an outstanding substrate for developing new sensors with the highest sensitivity against SARS-CoV-2.

Atomistic simulations suggest dietary flavonoids from Beta vulgaris (beet) as promising inhibitors of human angiotensin-converting enzyme and 2-alpha-adrenergic receptors in hypertension.

Beta vulgaris (beet) is extensively reported for its antihypertensive activity. However, the mechanismunderpinning its antihypertensive activity is not well understood. In this study, we evaluated the in silico interactionsof 70 compounds derived from beta vulgaris against the active sites of angiotensin-converting enzyme (ACE) and alpha-adrenergic receptor (AR). Structure-based virtual screening against angiotensin-converting enzyme revealed that, Cochliophilin A (-9.0Kcal/mol), Miraxanthin (-8.3Kcal/mol), and quercimeritrin (-9.7Kcal/mol) had lower docking scores than the reference lisinopril (-7.9Kcal/mol). These compounds exhibited dual binding tendency as they also ranked top compounds upon screening against adrenergic receptor. The thermodynamic parameters computed from the resulting trajectories obtained from the 100 ns full atomistic molecular dynamics simulation revealed structural stability and conformational flexibility of the ligand-receptor complexes as indicated by the RMSD, RMSF, RoG, SASA, and H-bond calculations. The molecular mechanics with generalized Born and surface area solvation binding energy calculations revealed that the proteins exhibit considerable binding energy with the phytochemicals in a dynamic environment. Furthermore, the hit compounds possess good physicochemical properties and drug-likeness. Overall, cochliophilin and quercimeritrin are promising dual-target directed flavonoids from Beta vulgaris; and are suggested for further experimental and preclinical evaluation. All data was provided in the manuscript.

Electro-detachment of kinesin motor domain from microtubule in silico

Kinesin is a motor protein essential in cellular functions, such as intracellular transport and cell-division, as well as for enabling nanoscopic transport in bio-nanotechnology. Therefore, for effective control of function for nanotechnological applications, it is important to be able to modify the function of kinesin. To circumvent the limitations of chemical modifications, here we identify another potential approach for kinesin control: the use of electric forces. Using full-atom molecular dynamics simulations (247,358 atoms, total time ∼ 4.4 μs), we demonstrate, for the first time, that the kinesin-1 motor domain can be detached from a microtubule by an intense electric field within the nanosecond timescale. We show that this effect is field-direction dependent and field-strength dependent. A detailed analysis of the electric forces and the work carried out by electric field acting on the microtubule–kinesin system shows that it is the combined action of the electric field pulling on the β-tubulin C-terminus and the electric-field-induced torque on the kinesin dipole moment that causes kinesin detachment from the microtubule. It is shown, for the first time in a mechanistic manner, that an electric field can dramatically affect molecular interactions in a heterologous functional protein assembly. Our results contribute to understanding of electromagnetic field–biomatter interactions on a molecular level, with potential biomedical and bio-nanotechnological applications for harnessing control of protein nanomotors.

Antioxidant and Neuroprotective Effects of the First Tryptophyllin Found in Snake Venom (Bothrops moojeni)

In this study, we report the isolation, characterization, and synthesis of the peptide BmT-2 belonging to the tryptophyllins family, isolated from the venom of the snake Bothrops moojeni. This is the first time a tryptophyllin is identified in snake venom. We tested whether BmT-2 had cytotoxic effects and antioxidant activity in a set of experiments that included both in vitro and cell-based assays. BmT-2 presented a radical scavenging activity toward ABTS• and AAPH-derived radicals. BmT-2 protected fluorescein, DNA molecules, and human red blood cells (RBCs) from free radicals generated by the thermal decomposition of AAPH. The novel tryptophyllin was not toxic in cell viability tests, where it (up to 0.4 mg/mL) did not cause hemolysis of human RBCs and did not cause significant loss of cell viability, showing a CC50 > 1.5 mM for cytotoxic effects against SK-N-BE(2) neuroblastoma cells. BmT-2 prevented the arsenite-induced upregulation of Nrf2 in Neuro-2a neuroblasts and the phorbol myristate acetate-induced overgeneration of reactive oxygen species and reactive nitrogen species in SK-N-BE(2) neuroblastoma cells. Electronic structure calculations and full atomistic reactive molecular dynamics simulations revealed the relevant contribution of aromatic residues in BmT-2 to its antioxidant properties. Our study presents a novel peptide classified into the family of the tryptophyllins, which has been reported exclusively in amphibians. Despite the promising results on its antioxidant activity and low cytotoxicity, the mechanisms of action of BmT-2 still need to be further elucidated.

Active responses of nanoparticle-polymer interface/interphase via the interfacial interaction redistribution

Physical responses of nanoparticle (NP)-polymer interphase/interface to external stimulus are a topic of great interest in nanocomposites. Previously, the interphase was tacitly assumed to have passive responses with constant material properties during deformation while the interface was mainly studied under hydrostatic loadings. To explore the unique features of the interphase we used a full-atom molecular dynamics simulation to monitor the evolution of its mass density and atomic stress profiles during deformation. A cohesive zone model was then used to define the key parameters for the NP-polymer interaction, which enable one to study the responses of the interface without spherical symmetry and understand the unique behavior of the stretched interphase/interface. The conceptual change has been achieved showing that an external strain can redistribute the NP-polymer interaction to affect the high compression in the interphase, the physical origin of the interface confinement effect in the nanocomposite. This eventually triggers the active responses of the interphase leading to the apparent strain-dependence of the mass density and some other properties. The redistribution of the interfacial interaction also brings about the stable, metastable and unstable status of the stretched interface characterized by the strain-dependent modulus and interface debonding.

Suspended water nanodroplets evaporation and its deviation from continuum estimations

Although droplets evaporation is fundamental to many applications and phenomena, accurate prediction of their evaporation trajectory is still a technological gap today. This is even more so for nanodroplets when compared to the macro-sized droplets. Since it is technically challenging to observe real nanodroplets evaporation today, this contribution uses full atomistic molecular dynamics simulations to observe and quantify suspended water nanodroplets evaporation. There are two main findings to this contribution. First, it is shown in detail that continuum analysis significantly over predicts the evaporation rate of nanodroplets. This makes continuum analysis unsuitable to predict water nanodroplets’ behavior. Secondly, this contribution illustrates the use of data-driven approach that can be used for nanodroplets evaporation behavior prediction, instead of running full atomistic molecular dynamics simulations for every different condition, which can be prohibitively expensive. The paper hopes to encourage scientists working in similar field to share their MD results for nanodroplets evaporation to build a data-driven model that could be used to predict nanodroplets evaporation trajectory at a fraction of the cost of full-scale MD simulations.

Multiscale bridging method to characterize elasto-plastic properties of polymer nanocomposites

A multiscale bridging method is proposed to describe the elasto-plastic behavior of polymer nanocomposites affected with the interphase elasto-plastic constitutive law (near the nanoparticle). The inverse characterization method of the interphase elasto–plastic constitutive law was proposed by combining full atomistic molecular dynamics and finite element homogenization. Based on the proposed multiscale bridging method, the influences of the crosslink ratio of the epoxy network and radius of nanoparticles on the elasto-plastic behavior of the interphase were investigated. Additionally, a multiscale homogenization analysis of the representative volume element of the multi-particulate systems was conducted using the elasto–plastic constitutive law of interphase.

Structure and stability of polydiacetylene membrane systems: Molecular dynamics simulation studies

We have performed full atomistic molecular dynamics (MD) simulations to investigate structure and stability of bilayer membrane systems consisting of monomeric or polymeric 10,12-pentacosadiynoic acid (PCDA) units connected with lysine groups by amide bonds. The PCDA monomer molecules show a twisted three-rod-domain structure with two kinks but upon polymerization, they possess more elongated conformation. The resulting polydiacetylene (PDA) membrane systems have stable membrane structures at room temperature, which is similar to biological lipid bilayer membranes and maintain their gel-like membrane integrity even up to as high as 370 K. Structural properties such as area per monomer, membrane thickness, density profile, 2D pair distribution function, and orientational correlation function are also calculated to understand the membrane structure and check its stability upon thermal fluctuation with atomistic resolution. This study is expected to provide the understanding about PDA membrane systems in atomistic details as well as significant insights into designing new novel PDA sensors.

Evaluation of Microscopic Damage of PEEK Polymers under Cyclic Loadings Using Molecular Dynamics Simulations.

Full-atomic molecular dynamics simulations were conducted to investigate the time evolution of microscopic damage in polyetheretherketone (PEEK) polymers under cyclic loading conditions. Three characteristics were used to quantify microscopic damage: entropy, distribution of the end-to-end distance of polymers, and the volume fraction of voids. Our results show that the degree of disentanglement of polymers and the volume fraction of voids increase with cyclic loading, which may lead to entropy generation. Uniaxial tensile strength simulations of the polymer system before and after cyclic loading were performed. The tensile strength after cyclic loading was lower than that before loading. Furthermore, two systems with the same entropy and different loading histories showed almost the same strength. These results imply that entropy generation is expressed as the total microscopic damage and can potentially be employed for effective evaluation of the degradation of material characteristics.