Full-atom Molecular Dynamics Simulations Research Articles

Novel nonlinear coarse-grained potentials of carbon nanotubes

Centimetres-long carbon nanotube (CNT) bundles with tensile strength over 80 GPa have been fabricated and tested recently [Nat. Nanotechnol. 13, 589–595 (2018)], but it is still a tremendous challenge to predict their nonlinear mechanical behaviors by full-atom molecular dynamics (MD) due to the huge computational cost, particularly for carbon nanotube networks. We completely established here the explicit expressions of the chirality-dependent higher-order nonlinear coarse-grained stretching and bending potentials based on the full-atom Reactive Empirical Bond-Order interatomic potential of second generation (REBO potential). In particular, the coarse-grained non-bonded potentials are improved by using the 18–24 Lennard-Jones potential. By comparison with available experimental results and full-atom MD simulations as well as our analytical results, the present nonlinear coarse-grained potentials have high accuracy. The obtained nonlinear coarse-grained potentials can be used to efficiently characterize the nonlinear mechanical behaviors and understand the failure mechanism of the CNT bundles and networks with 2∼5 orders of magnitude reduction in computing time, which should be of great help for designing and assembling CNT-based flexible microdevices.

An efficient multiscale homogenization modeling approach to describe hyperelastic behavior of polymer nanocomposites

The mechanical characterization of the interphase zone has attracted considerable attention in the fields of mechanical engineering and material design. Especially, the constitutive modeling for the description of the nonlinear mechanical behaviors of the interphase zone within the finite strain is essential for the material design of the polymer nanocomposites (e.g., the thermo-mechanical design, the fracture toughness design, and the fatigue life design). In this study, we propose an efficient multiscale homogenization modeling approach to describe the hyperelastic behavior of the polymer nanocomposites. This is the first attempt to achieve the hyperelastic constitutive modeling of the interphase zone by the multiscale framework, which is based on the full-atomistic molecular dynamics simulations and the multiscale homogenization analysis. The role of interfacial interactions between the nanoparticle and the polymer matrix on the nonlinear mechanical behaviors of polymer nanocomposites is characterized within the finite strain range by the proposed multiscale framework. To overcome the numerical inefficiencies induced by the excessively large number of iterations, the proper orthogonal decomposition method is merged into the proposed multiscale framework. The equivalent continuum models of the polymer nanocomposites are verified by the full atomistic molecular dynamics simulations.

A multiscale model of mechanotransduction by the ankyrin chains of the NOMPC channel.

Our senses of touch and hearing are dependent on the conversion of external mechanical forces into electrical impulses by the opening of mechanosensitive channels in sensory cells. This remarkable feat involves the conversion of a macroscopic mechanical displacement into a subnanoscopic conformational change within the ion channel. The mechanosensitive channel NOMPC, responsible for hearing and touch in flies, is a homotetramer composed of four pore-forming transmembrane domains and four helical chains of 29 ankyrin repeats that extend 150 Å into the cytoplasm. Previous work has shown that the ankyrin chains behave as biological springs under extension and that tethering them to microtubules could be involved in the transmission of external forces to the NOMPC gate. Here we combine normal mode analysis (NMA), full-atom molecular dynamics simulations, and continuum mechanics to characterize the material properties of the chains under extreme compression and extension. NMA reveals that the lowest-frequency modes of motion correspond to fourfold symmetric compression/extension along the channel, and the lowest-frequency symmetric mode for the isolated channel domain involves rotations of the TRP domain, a putative gating element. Finite element modeling reveals that the ankyrin chains behave as a soft spring with a linear, effective spring constantof 22 pN/nm for deflections ≤15 Å. Force-balance analysis shows that the entire channel undergoes rigid body rotation during compression, and more importantly, each chain exerts a positive twisting moment on its respective linker helices and TRP domain. This torque is a model-independent consequence of the bundle geometry and would cause a clockwise rotation of the TRP domain when viewed from the cytoplasm. Force transmission to the channel for compressions >15 Å depends on the nature of helix-helix contact. Our work reveals that compression of the ankyrin chains imparts a rotational torque on the TRP domain, which potentially results in channel opening.

Force Transduction in the NOMPC Mechanosensitive Channel

The recent structure of the NOMPC mechanosensitive channel, responsible for hearing and touch in fly, provides a great opportunity to understand how external mechanical forces are converted into electrical impulses through the opening of ion channels in sensory cells. NOMPC is a homo-tetramer composed of a transmembrane domain containing the ion channel pore and a cytoplasmic domain made up of 4 helical chains of 150 Å length. The chains made of 29 Ankyrin repeats come into contact with each other at two points and associate with microtubules. The transmission of external forces responsible for NOMPC gating is believed to occur by tethering the Ankyrin chains to microtubules. Previous work has demonstrated that isolated Ankyrin chains behave as biological springs under extension. Here, we combine full-atom molecular dynamics simulations, normal mode analysis (NMA), and continuum mechanics to characterize the material properties of the chains under extreme compression and extension. The NMA reveals that the lowest energy modes correspond to 4-fold symmetric compression/extension along the long-axis of the channel parallel to the membrane normal, while higher energy modes correspond to symmetric displacements of the TRP domain in the channel. The finite element model reveals that the Ankyrin chains behave as a soft spring with a linear restoring force of ∼4 pN/nm for deflections ≤15 Å, and as a non-linear spring for larger deformations. Detailed force-balance analysis on the chains during compression reveal that they exert a clockwise twisting moment on the TRP domain when viewed from the cytoplasm, which is solely a consequence of the bundle geometry. This rotation of the TRP domain is consistent with the gating mechanism suggested for the closely related TRPV1 ion channel based on open and closed structure.

Defect sensitivity and Weibull strength analysis of monolayer silicene

This paper analyzes ultimate tensile stress results from full atomistic reactive molecular dynamics (MD) simulations of monolayer silicene in terms of reliability using the Weibull probability of failure method (e.g., Weibull strength analysis). Both vacancy and interstitial defects and randomly distributed with prescribed densities upon a finite sheet of silicene and assessed for tension in both the zigzag and armchair directions, resulting in a significant decrease of strength. We demonstrate a clear directional dependency on the effect: mechanical properties in the zigzag direction are the most affected for both defect types. A single vacancy reduces the ultimate in-plane stress by approximately 13%, and one interstitial/adatom resulted in a strength reduction on the order of 24%, compared to the pristine state. Statistical analysis for the tensile strengths of indicate a Weibull modulus (m) on the order of approximately 50–150 depending on defect type and loading direction, using a best-fit approach via a Poisson distribution of defects, suggesting relatively high flaw tolerance once defects are present. Weibull analysis provides a method for determining the reliability of strength measurements in the analysis of data from future experimental assays of silicene.

Selective permeability of biphenylene carbon (BPC) membrane

Biphenylene carbon is a porous carbon allotrope with a thickness of a single atom. An open question is wheter the BPC natural porosity can be exploited to create selective permeable membranes. We have carried out full atomistic Molecular Dynamics simulations to show that BPC is highly selective for H2. We have also investigated its possible application for H2 purification.

New Binding Mode of SLURP Protein to a7 Nicotinic Acetylcholine Receptor Revealed by Computer Simulations

SLURP-1 is a member of three-finger toxin-like proteins. Their characteristic feature is a set of three beta strands extruding from hydrophobic core stabilized by disulfide bonds. Each beta-strand carries a flexible loop, which is responsible for recognition. SLURP-1 was recently shown to act as an endogenous growth regulator of keratinocytes and tumor suppressor by reducing cell migration and invasion by antagonizing the pro-malignant effects of nicotine. This effect is achieved through allosteric interaction with alpha7 nicotinic acetylcholine receptors (alpha-7 nAChRs) in an antagonist-like manner. Moreover, this interaction is unaffected by several well-known agents specifically alpha-bungarotoxin. In this work, we carry out the conformational analysis of the SLURP-1 by a microsecond-long full-atom explicit solvent molecular dynamics simulations followed by clustering, to identify representative states. To achieve this timescale we employed a GPU-accelerated version of GROMACS modeling package. To avoid human bias in clustering we used a non-parametric clustering algorithm Affinity Propagation adapted for biomolecules and HPC environments. Then, we applied protein-protein molecular docking of the ten most massive clusters to alpha7-nAChRs in order to test if structural variability can affect binding. Docking simulations revealed the unusual binding mode of one of the minor SLURP-1 conformations.

A computational and experimental approach to develop minocycline-imprinted hydrogels and determination of their drug delivery performances

In this study, minocycline-imprinted hydrogels are developed for controlled drug delivery in ocular disease treatments. An integrated computational and experimental study are conducted for investigating the relationship between design parameters and the drug loading/release performance of hydrogels. First, suitable functional monomers are determined for successful drug-imprinting by studying pre-polymerization conditions with full-atom molecular dynamics (MD) simulations. MD simulations suggest that acrylic acid and itaconic acid are suitable monomers for imprinting minocycline. Then, minocycline-imprinted hydrogels are synthesized with acrylic acid, commonly used in hydrogels, and three different amounts of cross-linker ethylene glycol dimethacrylate, 1, 2 and 3 mol%. All hydrogels are characterized and their drug loading and release performances are determined. Our computational and experimental calculations indicate an optimum cross-linker amount of 2 mol% for controlled minocycline release from imprinted hydrogels with an imprinting factor of almost 3. Finally, the drug release kinetics are determined by Korsmeyer-Peppas model.

Modeling of the Functionalized Gold Nanoparticle Aggregation in the Presence of Dopamine: A Joint MD/QM Study

The investigation of gold nanoparticle (AuNP) aggregation at the atomic level is a great challenge from the experimental view, while theoretical methods facilitate our understanding of the AuNP aggregation process. In this article, by applying full atomistic molecular dynamics simulations, the aggregation process and the stability of the functionalized AuNPs with 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (AT) was investigated. Moreover, the ability of AT–AuNPs toward selective detection of dopamine was analyzed. Theoretical results showed that AT groups on the surface of the AuNPs increase the resistance of nanoparticles against the aggregation. Also, AT–AuNPs are only accumulated in the presence of dopamine in a mixture of different analytes. In this process, dopamine acts as a molecular bridge between the AT–AuNPs, which facilitates nanoparticle aggregation through hydrogen bond interactions. Quantum chemistry calculations confirmed that the structural feature of dopamine is a more effective factor ...

Redox-coupled quinone dynamics in the respiratory complex I

Complex I couples the free energy released from quinone (Q) reduction to pump protons across the biological membrane in the respiratory chains of mitochondria and many bacteria. The Q reduction site is separated by a large distance from the proton-pumping membrane domain. To address the molecular mechanism of this long-range proton-electron coupling, we perform here full atomistic molecular dynamics simulations, free energy calculations, and continuum electrostatics calculations on complex I from Thermus thermophilus We show that the dynamics of Q is redox-state-dependent, and that quinol, QH2, moves out of its reduction site and into a site in the Q tunnel that is occupied by a Q analog in a crystal structure of Yarrowia lipolytica We also identify a second Q-binding site near the opening of the Q tunnel in the membrane domain, where the Q headgroup forms strong interactions with a cluster of aromatic and charged residues, while the Q tail resides in the lipid membrane. We estimate the effective diffusion coefficient of Q in the tunnel, and in turn the characteristic time for Q to reach the active site and for QH2 to escape to the membrane. Our simulations show that Q moves along the Q tunnel in a redox-state-dependent manner, with distinct binding sites formed by conserved residue clusters. The motion of Q to these binding sites is proposed to be coupled to the proton-pumping machinery in complex I.

Tethered multifluorophore motion reveals equilibrium transition kinetics of single DNA double helices

We describe a tethered multifluorophore motion assay based on DNA origami for revealing bimolecular reaction kinetics on the single-molecule level. Molecular binding partners may be placed at user-defined positions and in user-defined stoichiometry; and binding states are read out by tracking the motion of quickly diffusing fluorescent reporter units. Multiple dyes per reporter unit enable singe-particle observation for more than 1 hour. We applied the system to study in equilibrium reversible hybridization and dissociation of complementary DNA single strands as a function of tether length, cation concentration, and sequence. We observed up to hundreds of hybridization and dissociation events per single reactant pair and could produce cumulative statistics with tens of thousands of binding and unbinding events. Because the binding partners per particle do not exchange, we could also detect subtle heterogeneity from molecule to molecule, which enabled separating data reflecting the actual target strand pair binding kinetics from falsifying influences stemming from chemically truncated oligonucleotides. Our data reflected that mainly DNA strand hybridization, but not strand dissociation, is affected by cation concentration, in agreement with previous results from different assays. We studied 8-bp-long DNA duplexes with virtually identical thermodynamic stability, but different sequences, and observed strongly differing hybridization kinetics. Complementary full-atom molecular-dynamics simulations indicated two opposing sequence-dependent phenomena: helical templating in purine-rich single strands and secondary structures. These two effects can increase or decrease, respectively, the fraction of strand collisions leading to successful nucleation events for duplex formation.

Simulation of Mixed Self-Assembled Monolayers on Gold: Effect of Terminal Alkyl Anchor Chain and Monolayer Composition

Self-assembling monolayers provide a reproducible synthetic microenvironment for tethering lipid bilayers to incorporate proteins and lay the ground for numerous applications in nanotechnology and biomedical engineering. Although the structure of single-component monolayers is well investigated, there is far less insight into the molecular behavior at the interface of mixed monolayers at different mole fractions. Here, we present and apply a novel procedure to simulate and analyze multicomponent self-assemblies of alkanethiols over a wide range of mole concentrations of anchoring compounds. In particular, the structural features of monolayers consisting of a matrix compound and either a short (C8) or a long (C16) anchor compound on Au(111)-like surfaces were investigated first using coarse-grained and subsequently full-atomistic molecular dynamics simulations. Different scenarios of spatial distributions (random vs clustering) of anchoring molecules on flat surfaces were probed. The results of the simulations are in excellent agreement with the experimental data from ellipsometry and infrared reflection absorption spectroscopy. For short anchoring molecules, a random spatial distribution in the matrix is obtained. At low, experimentally relevant anchor compound mole fractions < 0.1, only for long-chain (C16)-terminal alkyls, phase segregation and self-association of the anchoring molecules can be observed, which are also seen in experiment.

Molecular dynamics simulations suggest why the A2058G mutation in 23S RNA results in bacterial resistance against clindamycin

Clindamycin, a lincosamide antibiotic, binds to 23S ribosomal RNA and inhibits protein synthesis. The A2058G mutation in 23S RNA results in bacterial resistance to clindamycin. To understand the influence of this mutation on short-range interactions of clindamycin with 23S RNA, we carried out full-atom molecular dynamics simulations of a ribosome fragment containing clindamycin binding site. We compared the dynamical behavior of this fragment simulated with and without the A2058G mutation. Molecular dynamics simulations suggest that clindamycin in the native ribosomal binding site is more internally flexible than in the A2058G mutant. Only in the native ribosome fragment did we observe intramolecular conformational change of clindamycin around its C7-N1-C10-C11 dihedral. In the mutant, G2058 makes more stable hydrogen bonds with clindamycin hindering its conformational freedom in the ribosome-bound state. Clindamycin binding site is located in the entrance to the tunnel through which the newly synthesized polypeptide leaves the ribosome. We observed that in the native ribosome fragment, clindamycin blocks the passage in the tunnel entrance, whereas in the mutated fragment the aperture is undisturbed due to a different mode of binding of clindamycin in the mutant. Restricted conformational freedom of clindamycin in a position not blocking the tunnel entrance in the A2058G mutant could explain the molecular mechanism of bacterial resistance against clindamycin occurring in this mutant.

Molecular Dynamics Simulation to Reveal Effects of Binder Content on Pt/C Catalyst Coverage in a High-Temperature Polymer Electrolyte Membrane Fuel Cell

Full atomistic molecular dynamics simulations were performed to provide detailed information on the morphologies of Pt/C catalyst with varying poly(tetrafuoroethylene) (PTFE) binder contents. Changes in the surface configuration and PTFE coverage on Pt particles with changing binder content were examined on the molecular level; this coverage can affect the catalytic performance of Pt particles and PTFE binding. The PTFE binder content in the prepared solutions ranged from 4.0 to 35.1 wt %. From Pt-PTFE pair correlation analysis, the coordination number of this pair increased from 0.43 to 1.23 as the PTFE binder content increased from 4.0 to 35.1 wt %, with a concomitant 40.0 to 84.0% change in coverage over the Pt surface. At low PTFE content, the PTFE binder was dispersed between Pt particles and the carbons on the Pt/C surface to form a triple-phase boundary. Subsequently, Pt particles become increasingly covered by PTFE with increasing binder content. However, no significant changes were observed when ...

Local orientational mobility of polyimide-based nanocomposites

In the present study, the influence of filler concentration on the dynamic properties of nanocomposites based on the thermoplastic polyimide R-BAPO has been investigated by means of full-atomistic molecular dynamics simulations. The orientational mobility of chain fragments of different lengths has been studied before and after embedding of single-walled carbon nanotubes (SWCNT) into the polymer. Slowing down of the polymer orientational mobility in nanocomposites at temperature T = 600 K above the glass transition temperature has been observed for all considered chain fragments in comparison to unfilled systems. It was found that the relative increase of the rotation relaxation times in the diamine part of R-BAPO in the presence of SWCNT is higher for longer chain fragments. This result is in agreement with recent experimental data and with theoretical predictions for the composites based on homopolymers. On the other hand, the relative change of rotation relaxation times under filler loading in the dianhydride part of R-BAPO demonstrates non-monotonic dependence on the length of chain fragments. This result may be explained by structural inhomogeneity of the dianhydride part. Slowing down of the orientational mobility is accompanied by the increase of the glass transition temperature of the composites on ca. 5–15 K with increase of the nanofiller concentration on ca. 3–6% of mass fraction.

Stretch-Induced Coil–Helix Transition in Isotactic Polypropylene: A Molecular Dynamics Simulation

The stretch-induced coil–helix transition (CHT) of isotactic polypropylene (iPP) was studied with full-atom molecular dynamics (MD) simulations during the uniaxial stretch process. The results show that imposing stretch induces CHT, which increases both the content and the average length of helices. As strain exceeding a certain value, long helices initially not presented in melt start to emerge, which mainly follow a kinetic pathway of merging adjacent short helices, while overstretch at large strain leads to the helix-extended coil transition. Based on statistics on the distribution of helical length and theoretical calculation, stretch is found to reduce free energy gap for CHT. At small strain, the single-chain model is sufficient to account stretch-induced CHT for the formation of short helices, but the gap reduction is mainly contributed by intrachain energy rather than entropy, which is different from current theories for stretch-induced CHT. While the formation of long helices at large strain requ...

Molecular Dynamics Simulation of 4-N-Hexyl-4’-Cyanobiphenyl Adsorbed at the Air-Water Interface

The interfacial behavior of 4-n-hexyl-4’-cyanobiphenyl (6CB) molecules at the air-water interface is investigated by full atomistic molecular dynamics simulations. To understand the morphology and the structure of adsorbed 6CB molecules in detail, the snapshots and mass density profiles of the simulation system are generated. The average tilt angles between the interface normal and various vectors defined in the rigid and alkyl parts of 6CB are in good agreement with the experimental data available. The interfacial thickness and monolayer width are obtained from the mass density profiles of water and 6CB phase, respectively. The second and fourth rank orientational order parameters of cyanobiphenyl core are found to be larger than those of an elastic alkyl chain. Bond order parameters for 6CB are also calculated. The calculated oxygen-oxygen radial distribution function and hydrogen bonding statistics for bulk water are compared with those for the interfacial region. The surface tensions of the systems are calculated. All simulation results are compared with the available literature data.

Evolutionary conservation of the allosteric activation of factor VIIa by tissue factor in lamprey

Background Previous studies have provided insight into the molecular basis of human tissue factor (TF) activation of activated factor VII (FVIIa). TF-induced allosteric networks of FVIIa activation have been rationalized through analysis of the dynamic changes and residue connectivities in the human soluble TF (sTF)/FVIIa complex structure during molecular dynamics (MD) simulation. Evolutionary conservation of the molecular mechanisms for TF-induced allosteric FVIIa activation between humans and extant vertebrate jawless fish (lampreys), where blood coagulation emerged more than 500 million years ago, is unknown and of considerable interest. Objective To model the sTf/FVIIa complex from cloned Petromyzon marinus lamprey sequences, and with comparisons to human sTF/FVlla investigate conservation of allosteric mechanisms of FVIIa activity enhancement by soluble TF using MD simulations. Methods Full-length cDNAs of lamprey tf and f7 were cloned and characterized. Comparative models of lamprey sTf/FVIIa complex and free FVIIa were determined based on constructed human sTF/FVIIa complex and free FVIIa models, used in full-atomic MD simulations, and characterized using dynamic network analysis approaches. Results Allosteric paths of correlated motion from Tf contact points in lamprey sTf/FVIIa to the FVIIa active site were determined and quantified, and were found to encompass residue-residue interactions along significantly similar paths compared with human. Conclusions Despite low conservation of residues between lamprey and human proteins, 30% TF and 39% FVII, the structural and protein dynamic effects of TF activation of FVIIa appear conserved and, moreover, present in extant vertebrate proteins from 500 million years ago when TF/FVIIa-initiated extrinsic pathway blood coagulation emerged.

Molecular origins of elastoplastic behavior of polycarbonate under tension: A coarse-grained molecular dynamics approach

Polycarbonate (PC) is an important engineering polymer that has been used as the structural material in a wide range of applications. Using coarse-grained (CG) molecular dynamics (MD), this work systematically investigates the elastoplastic deformation of PC under two tension scenarios. To drastically improve computational efficiency, a new CG force field is developed for PC based on full-atom MD simulations. Effectiveness of the force field is verified by the calculations of glass transition temperature, Young’s modulus, strength, and distribution functions of bond stretching, bending and torsion. Using the newly developed force field, PC is found to undergo elastic deformation followed by the onset of yielding and plastic flow, in both uniaxial tension and constrained tension. The onset of yielding and plastic deformation are correlated with structural evolution using MD snapshots. Energy variations associated with bond stretching, bending and torsion are further analyzed to provide insights into their respective contributions to the deformation process. MD results are further compared with Argon’s model, which does not only accurately predict the mechanical strength of PC, but also provides molecular-level insights into the deformation mechanisms.

Metal ions affect the formation and stability of amyloid β aggregates at multiple length scales.

Amyloid β (Aβ) aggregates, which are a hallmark for neurodegenerative disease, are formed through a self-assembly process such as aggregation of Aβ peptide chains. This aggregation process depends on the solvent conditions under which the proteins are aggregated. Nevertheless, the underlying mechanism of the ionic effect on the formation and stability of amyloid aggregates has not been fully understood. Here, we report how metal ions play a role in the formation and stability of Aβ aggregates at different length scales, i.e. oligomers and fibrils. It is shown that the metal (i.e. zinc or copper) ion increases the stability of Aβ oligomers, whereas the metal ion reduces the stability of Aβ fibrils. In addition, we found that zinc ions are able to more effectively destabilize fibril structures than copper ions. Metal ion-mediated (de)stabilization of Aβ oligomers (or fibrils) is attributed to the critical effect of the metal ion on the β-sheet rich crystalline structure of the amyloid aggregate and the status of hydrogen bonds within the aggregate. Our study sheds light on the role of the metal ion in stabilizing the amyloid oligomers known as a toxic agent (to functional cells), which is consistent with clinical observation that high concentrations of metal ions are found in patients suffering from neurodegenerative diseases.