Force Molecular Dynamics Simulations Research Articles

Ion-Specific and pH-Dependent Hydration of Mica-Electrolyte Interfaces.

Hydration forces play a crucial role in a wide range of phenomena in physics, chemistry, and biology. Here, we study the hydration of mica surfaces in contact with various alkali chloride solutions over a wide range of concentrations and pH values. Using atomic force microscopy and molecular dynamics simulations, we demonstrate that hydration forces consist of a superposition of a monotonically decaying and an oscillatory part, each with a unique dependence on the specific type of cation. The monotonic hydration force gradually decreases in strength with decreasing bulk hydration energy, leading to a transition from an overall repulsive (Li+, Na+) to an attractive (Rb+, Cs+) force. The oscillatory part, in contrast, displays a binary character, being hardly affected by the presence of strongly hydrated cations (Li+, Na+), but it becomes completely suppressed in the presence of weakly hydrated cations (Rb+, Cs+), in agreement with a less pronounced water structure in simulations. For both aspects, K+ plays an intermediate role, and decreasing pH follows the trend of increasing Rb+ and Cs+ concentrations.

Hysteretic order-disorder transitions of ionic liquid double layer structure on graphite

Understanding the electrical double layer (EDL) structure at the solid/liquid interface is critical towards realizing the full potential of electrochemical applications using ionic liquids. In this work, the out-of-plane and in-plane EDL structures of PYR14-TFSI on graphite (HOPG) have been studied by in-situ electrochemical atomic force microscopy (AFM) and molecular dynamics (MD) simulation. AFM results revealed that the first adsorbed ion layer on HOPG consists of both disordered and ordered lateral domains. It has been found that the neighboring molecules in the x-y plane form intricate ordered lateral structures on length scale of hundreds of nanometers, and the out-of-plane EDL structure is independent of the in-plane structure. MD simulations under zero polarization showed that in the first adsorbed layer, cations have one preferred orientation while anions have two preferred orientations in relation to the HOPG surface, which might be the origin of the complex lateral ordering. When polarizing the surface, a hysteretic order-disorder transition of the lateral ordering in the first adsorbed layer can be observed by in-situ AFM, and the ordered domains disappear for high positive or negative voltages. Comparison with bias-dependent MD reveals that the existence of a bimodal anion distribution in the first absorbed layer can be linked to the observed transitions giving new insights into the origin of the structural domains, which can help understand unusual charge and discharge kinetics observed in similar systems.

An algorithm for computing short-range forces in molecular dynamics simulations with non-uniform particle densities

We present projection sorting, an algorithmic approach to determining pairwise short-range forces between particles in molecular dynamics simulations. We show it can be more effective than the standard approaches when particle density is non-uniform. We implement tuned versions of the algorithm in the context of a biophysical simulation of chromosome condensation, for the modern Intel Broadwell and Knights Landing architectures, across multiple nodes. We demonstrate up to 5× overall speedup and good scaling to large problem sizes and processor counts.

Classical Pauli repulsion: An anisotropic, atomic multipole model.

Pauli repulsion is a key component of any theory of intermolecular interactions. Although Pauli or exchange repulsion has its origin in the quantum mechanical nature of electrons, it is possible to describe the resulting energetic effects via a classical model in terms of the overlap of electron densities. In fact, closed shell intermolecular repulsion can be explained as a diminution of election density in the internuclear region resulting in decreased screening of nuclear charges and increased nuclear-nuclear repulsion. We provide a concise anisotropic repulsion formulation using the atomic multipoles from the Atomic Multipole Optimized Energetics for Biomolecular Applications force field to describe the electron density at each atom in a larger system. Mathematically, the proposed model consists of damped pairwise exponential multipolar repulsion interactions truncated at short range, which are suitable for use in compute-intensive biomolecular force fields and molecular dynamics simulations. Parameters for 26 atom classes encompassing most organic molecules are derived from a fit to Symmetry Adapted Perturbation Theory exchange repulsion energies for the S101 dimer database. Several applications of the multipolar Pauli repulsion model are discussed, including noble gas interactions, analysis of stationary points on the water dimer potential surface, and the directionality of several halogen bonding interactions.

Single-Molecule Force Spectroscopy and Molecular Dynamics Simulations Reveals Complex Folding Landscape and its Potential Role in Amyloid Fibril Formation in a PDZ Domain

Single-Molecule Force Spectroscopy and Molecular Dynamics Simulations Reveals Complex Folding Landscape and its Potential Role in Amyloid Fibril Formation in a PDZ Domain

Elucidating Complimentary Base Specificity of Thymine DNA Glycosylase via Potential of Mean Force Molecular Dynamics Simulations

Elucidating Complimentary Base Specificity of Thymine DNA Glycosylase via Potential of Mean Force Molecular Dynamics Simulations

Assembly of peptides in mica-graphene nanocapillaries controlled by confined water.

Water in nanoscale-confined geometries has unique physicochemical properties in contrast to bulk water, and is believed to play important roles in biological processes although there is less direct information available in the literature. Here, we report the self-assembly behaviors of a neurodegenerative disease related peptide termed GAV-9 encapsulated in mica-graphene nanocapillaries interacting with water nanofilms condensed under ambient conditions, based on atomic force microscopy (AFM) imaging and molecular dynamics (MD) simulations. The results revealed that, upon increase in the humidity, the GAV-9 peptide monomers adsorbed the confined water molecules and transitioned to unexpected hydrogel-like structures. Our MD simulations also suggested that in the confined mica-graphene nanocapillaries, the GAV-9 peptide monomers would indeed form water-rich hydrogel structures instead of highly ordered nanofilaments. The interfacial water confined in the mica-graphene nanocapillary is found to be crucial for such a transition. Moreover, the distribution of confined water layers largely depended on the locations of the preformed peptide nanofilaments, and the peptide nanofilaments further assembled into nanosheets with the water layer increasing, but depolymerized to amorphous peptide assemblies with the water layer decreasing. The polymerization and depolymerization of the peptide nanofilaments could be controlled in a reversible manner. Our results have supplied a simplified model system to uncover the effects of the confined interfacial water on the biological process at the molecular level.

Deciphering multivalent glycocluster-lectin interactions through AFM characterization of the self-assembled nanostructures.

Pseudomonas aeruginosa is a human opportunistic pathogen responsible for lung infections in cystic fibrosis patients. The emergence of resistant strains and its ability to form a biofilm seem to give a selective advantage to the bacterium and thus new therapeutic approaches are needed. To infect the lung, the bacterium uses several virulence factors, like LecA lectins. These proteins are involved in bacterial adhesion due to their specific interaction with carbohydrates of the host epithelial cells. The tetrameric LecA lectin specifically binds galactose residues. A new therapeutic approach is based on the development of highly affine synthetic glycoclusters able to selectively link with LecA to interfere with the natural carbohydrate-LecA interaction. In this study, we combined atomic force microscopy imaging and molecular dynamics simulations to visualize and understand the arrangements formed by LecA and five different glycoclusters. Our glycoclusters are small scaffolds characterized by a core and four branches, which terminate in a galactose residue. Depending on the nature of the core and the branches, the glycocluster-lectin interaction can be modulated and the affinity increased. We show that glycocluster-LecA arrangements highly depend on the glycocluster architecture: the core influences the rigidity of the geometry and the directionality of the branches, whereas the nature of the branch determines the compactness of the structure and the ease of binding.

Understanding segregation processes in SAMs formed by mixtures of hydroxylated and non-hydroxylated fatty acids.

In this paper, we focus on the segregation processes emerging when preparing mixtures with different compositions of aleuritic (9,10,16 trihydroxyhexadecanoic) (ALE) and palmitic (hexadecanoic) (PAL) acids. The combination of atomic force microscopy (AFM) and molecular dynamics (MD) simulations enabled us to prove the role of the functional groups in the formation of self-assembled monolayers (SAMs) on muscovite mica surfaces. MD simulations indicate that segregation processes are favored in high ALE composition mixtures in agreement with the experimental evidence, whereas low ALE compositions promote the co-existence between segregated and dispersed systems. The secondary hydroxyl groups play a central role in the self-assembling mechanism because they control the formation of hydrogen bonding networks guarantying system stability.

Attachment, Coalescence, and Spreading of Carbon Dioxide Nanobubbles at Pyrite Surfaces.

Recently, it was reported that using CO2 as a flotation gas increases the flotation of auriferous pyrite from high carbonate gold ores of the Carlin Trend. In this regard, the influence of CO2 on bubble attachment at fresh pyrite surfaces was measured in the absence of collector using an induction timer, and it was found that nitrogen bubble attachment time was significantly reduced from 30 ms to less than 10 ms in CO2 saturated solutions. Details of CO2 bubble attachment at a fresh pyrite surface have been examined by atomic force microscopy (AFM) measurements and molecular dynamics (MD) simulations, and the results used to describe the subsequent attachment of a N2 bubble. As found from MD simulations, unlike the attached N2 bubble, which is stable and has a contact angle of about 90°, the CO2 bubble attaches, and spreads, wetting the fresh pyrite surface and forming a multilayer of CO2 molecules, corresponding to a contact angle of almost 180°. These MDS results are complemented by in situ AFM images, which show that, after attachment, CO2 nano-/microbubbles spread to form pancake bubbles at the fresh pyrite surface. In summary, it seems that CO2 bubbles have a propensity to spread, and whether CO2 exists as layers of CO2 molecules (gas pancakes) or as nano-/microbubbles, their presence at the fresh pyrite surface subsequently facilitates film rupture and attachment of millimeter N2 bubbles and, in this way, improves the flotation of pyrite.

Membrane-Modulating Drugs can Affect the Size of Amyloid-\u03b225\u201335 Aggregates in Anionic Membranes

The formation of amyloid-β plaques is one of the hallmarks of Alzheimer’s disease. The presence of an amphiphatic cell membrane can accelerate the formation of amyloid-β aggregates, making it a potential druggable target to delay the progression of Alzheimer’s disease. We have prepared unsaturated anionic membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) and added the trans-membrane segment Aβ25–35. Peptide plaques spontaneously form in these membranes at high peptide concentrations of 20 mol%, which show the characteristic cross-β motif (concentrations are relative to the number of membrane lipids and indicate the peptide-to-lipid ratio). We used atomic force microscopy, fluorescence microscopy, x-ray microscopy, x-ray diffraction, UV-vis spectroscopy and Molecular Dynamics (MD) simulations to study three membrane-active molecules which have been speculated to have an effect in Alzheimer’s disease: melatonin, acetylsalicyclic acid (ASA) and curcumin at concentrations of 5 mol% (drug-to-peptide ratio). Melatonin did not change the structural parameters of the membranes and did not impact the size or extent of peptide clusters. While ASA led to a membrane thickening and stiffening, curcumin made membranes softer and thinner. As a result, ASA was found to lead to the formation of larger peptide aggregates, whereas curcumin reduced the volume fraction of cross-β sheets by ~70%. We speculate that the interface between membrane and peptide cluster becomes less favorable in thick and stiff membranes, which favors the formation of larger aggregates, while the corresponding energy mismatch is reduced in soft and thin membranes. Our results present evidence that cross-β sheets of Aβ25–35 in anionic unsaturated lipid membranes can be re-dissolved by changing membrane properties to reduce domain mismatch.

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo.

Accurately predicting protein-ligand binding affinities and binding modes is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation time scales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes. In this technique, the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over 2 orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step toward applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding modes of ligands using enhanced sampling (BLUES) package which is freely available on GitHub.

Investigation of adhesive interactions in the specific targeting of Triptorelin-conjugated PEG-coated magnetite nanoparticles to breast cancer cells

The understanding of adhesive interaction at the nanoscale between functionalized nanoparticles and biological cells is of great importance to develop effective theranostic nanocarriers for targeted cancer therapy. Here, we report a combination of experimental and computational approaches to evaluate the adhesion between Triptorelin (a Luteinizing Hormone-Releasing Hormone (LHRH) agonist)-conjugated poly-(ethylene glycol) (PEG)-coated magnetite nanoparticles (Triptorelin-MNPs) and breast cells. The adhesion forces between Triptorelin-MNPs and normal/cancerous breast cells are obtained using atomic force microscopy. The corresponding work of adhesion is then estimated using Johnson-Kendall-Roberts model. Our results demonstrate that Triptorelin-MNPs have a fourteen-fold greater work of adhesion to breast cancer cells than to normal breast cells. In addition, the work of adhesion between Triptorelin-MNPs and breast cancer cells is found to be three times more than that between unmodified MNPs and breast cancer cells. Hence, the experimental observation indicates that Triptorelin ligands facilitate the specific targeting of breast cancer cells. Furthermore, molecular dynamics simulations are performed to investigate the molecular origins of the adhesive interactions. The simulations reveal that the interactions between molecules (e.g. Triptorelin and PEG) and LHRH receptors are dominated by van der Waals energies, while the interactions of these molecules with cell membrane are dominated by electrostatic interactions. Moreover, both experimental and computational results reveal that PEG serves as an effective coating that enhances adhesive interactions to breast cancer cells that over-express LHRH receptors, while reduces the adhesion to normal breast cells. Our results highlight the potential to develop Triptorelin-MNPs into tumor-specific MRI contrast agents and drug carriers. Statement of SignificanceSystematic investigation of adhesive interactions between functionalized nanoparticles and cancer cells is of great importance in developing effective theranostic nanocarriers for targeted cancer therapy. Herein, we use a combination of atomic force microscopy technique and molecular dynamics simulations approach to explore the adhesive interactions at the nanoscale between Triptorelin-conjugated polyethylene glycol (PEG)-coated magnetite nanoparticles and normal/cancerous breast cells. This study characterizes and quantifies the work of adhesion, as well as adhesion forces, at the nanocarrier/cell interfaces, unravels the molecular origins of adhesive interactions and highlights the effectiveness of PEG coatings and Triptorelin ligands in the specific targeting of breast cancer cells. Our findings expand the fundamental understanding of nanoparticle/cell adhesion and provide guidelines for the design of more rational nanocarriers.

Nanoscale Probing of Interaction in Atomically Thin Layered Materials.

We combine conductive atomic force microscopy (CAFM) and molecular dynamics (MD) simulations to reveal the interaction of atomically thin layered materials (ATLMs) down to nanoscale lateral dimension. The setup also allows quantifying, for the first time, the effect of layer number and electric field on the dielectric constant of ATLMs with few-layer down to monolayer thickness. Our CAFM-assisted electrostatic technique shows that high-quality mono- and bilayer graphene is reliably produced at significant yields only by the shear type of bond breaking between layers, whereas the normal type of bond breaking exhibits a very stochastic process mainly due to the coexistence of local delamination and interlayer twist. Our dielectric constant measurements also reveal a very weak dependence on the layer number and the electric field (up to our experimental limit of 0.1 V/Å), which is in contrast with theoretical reports. Owing to unexpectedly large variations in the screening ability of pristine monolayer graphene under ambient conditions, we further demonstrate that the effective dielectric constant of monolayer graphene can be engineered to provide a broad spectrum of dielectric responses (3.5–17) through oxidation and thermal annealing, thus confirming its much higher chemical reactivity than bilayer and few layers.

Probing Protein Folding Landscape by Using Combined Force Spectroscopy and Molecular Dynamics Simulations

Most proteins, even those with complex folding trajectories and rough energy landscapes, successfully navigate the funneled folding landscape to achieve the correct native conformations. However, some proteins misfold, sometimes resulting in some neurodegenerative diseases and cancers. Such misfolding is thought to occur via partially folded high-energy structures accessible from the native state or during the folding process. Structural and energetic characterization of such high-energy species is important but experimentally challenging due to their rare and transient nature under native conditions. Single-molecule force spectroscopy allows investigation of the force dependent movement of the transition state ensemble and detection of high-energy intermediates, which may be populated at high force. Molecular dynamics simulations allow atomistic characterization of structures and multiple folding pathways on the energy landscape. Here, we probe important protein sub-states and folding pathways of the second PDZ domain of PTP-BL by using a combination of single molecule optical tweezers experiments and molecular dynamics simulations.

Origin of hydration lubrication of zwitterions on graphene.

Formation of a hydration layer on charge sites can support normal pressure, and meanwhile it retains excellent fluidity to provide efficient boundary lubrication; however, it is limited to the sliding system between two similarly charged surfaces. In the present study, we report extremely low friction as the zwitterions in a lipid bilayer slide on the topmost graphene layer of graphite across pure water, with the friction coefficient falling to the level of 0.001, which provides direct evidence that hydration lubrication is effective even between such dissimilar surfaces. The origin of hydration lubrication on graphene was studied by atomic force microscopy and molecular dynamics simulation simultaneously. It reveals that a subnanometer hydration layer is confined between zwitterions and graphene, which remains as a liquid phase under normal pressure. The shear occurs between water molecules and graphene because of the extremely low shear strength of the water/graphene interface, which contributes to extremely low friction. Our finding demonstrates that the formation of a hydration layer is possible to lubricate layered materials efficiently, which has potential implications for designing efficient boundary lubrication with layered materials.

Single glucose molecule transport process revealed by force tracing and molecular dynamics simulations.

Transporting individual molecules across cell membranes is a fundamental process in cellular metabolism. Although the crystal diffraction technique has greatly contributed to our understanding of the structures of the involved transporters, a description of the dynamic transport mechanism at the single-molecule level has been extremely elusive. In this study, we applied atomic force microscopy (AFM)-based force tracing to directly monitor the transport of a single molecule, d-glucose, across living cell membranes. Our results show that the force to transport a single molecule of d-glucose across cell membranes is 37 ± 9 pN, and the corresponding transport interval is approximately 20 ms, while the average speed is approximately 0.3 μm s-1. Furthermore, our calculated force profile from molecular dynamics simulations showed quantitatively good agreement with the force tracing observation and revealed detailed information regarding the glucose transport path, indicating that two salt bridges, K38/E299 and K300/E426, play critical roles during glucose transport across glucose transporter 1 (GLUT1). This role was further verified using biological experiments that disrupted these two bridges and measured the uptake of glucose into the cells. Our approaches led to the first unambiguous description of the glucose transport process across cell membranes at the single-molecule level and demonstrated the biological importance of the two salt bridges for transporting glucose across GLUT1.

Single Molecule Force Spectroscopy and Molecular Dynamics Simulations as a Combined Platform for Probing Protein Face-Specific Binding

Biomolecular interactions frequently occur in orientation-specific manner. For example, prior nuclear magnetic resonance spectroscopy experiments in our lab have suggested the presence of a group of strongly binding residues on a particular face of the protein ubiquitin for interactions with Capto MMC multimodal ligands ("Capto" ligands) (Srinivasan, K.; et al. Langmuir 2014, 30 (44), 13205-13216). We present a clear confirmation of those studies by performing single-molecule force spectroscopy (SMFS) measurements of unbinding complemented with molecular dynamics (MD) calculations of the adsorption free energy of ubiquitin in two distinct orientations with self-assembled monolayers (SAMs) functionalized with "Capto" ligands. These orientations were maintained in the SMFS experiments by tethering ubiquitin mutants to SAM surfaces through strategically located cysteines, thus exposing the desired faces of the protein. Analogous orientations were maintained in MD simulations using suitable constraining methods. Remarkably, despite differences between the finer details of experimental and simulation methodologies, they confirm a clear preference for the previously hypothesized binding face of ubiquitin. Furthermore, MD simulations provided significant insights into the mechanism of protein binding onto this multimodal surface. Because SMFS and MD simulations both directly probe protein-surface interactions, this work establishes a key link between experiments and simulations at molecular scale through the determination of protein face-specific binding energetics. Our approach may have direct applications in biophysical systems where face- or orientation-specific interactions are important, such as biomaterials, sensors, and biomanufacturing.

Using atomic force microscopy and molecular dynamics simulation to investigate the asphalt micro properties

In this study, the asphalt microstructure and micro mechanical properties are first investigated using atomic force microscopy (AFM) experiments. The AFM experiment results show that the asphalt samples have very complex microstructure morphology. The molecular dynamics (MD) simulation is then conducted to model the asphalt molecular structure. A tension loading is applied on the asphalt structure. It is discovered that the structure will be gradually stretched and the potential energy for van der Waals interactions takes a major part in the total energy. The effect of molecules number on the MD results was analyzed. The phase field method was also used to simulate the micro mechanical properties considering the material viscoelasticity.

Organic-Silica Interactions in Saline: Elucidating the Structural Influence of Calcium in Low-Salinity Enhanced Oil Recovery

Enhanced oil recovery using low-salinity solutions to sweep sandstone reservoirs is a widely-practiced strategy. The mechanisms governing this remain unresolved. Here, we elucidate the role of Ca2+ by combining chemical force microscopy (CFM) and molecular dynamics (MD) simulations. We probe the influence of electrolyte composition and concentration on the adsorption of a representative molecule, positively-charged alkylammonium, at the aqueous electrolyte/silica interface, for four electrolytes: NaCl, KCl, MgCl2, and CaCl2. CFM reveals stronger adhesion on silica in CaCl2 compared with the other electrolytes, and shows a concentration-dependent adhesion not observed for the other electrolytes. Using MD simulations, we model the electrolytes at a negatively-charged amorphous silica substrate and predict the adsorption of methylammonium. Our simulations reveal four classes of surface adsorption site, where the prevalence of these sites depends only on CaCl2 concentration. The sites relevant to strong adhesion feature the O− silica site and Ca2+ in the presence of associated Cl−, which gain prevalence at higher CaCl2 concentration. Our simulations also predict the adhesion force profile to be distinct for CaCl2 compared with the other electrolytes. Together, these analyses explain our experimental data. Our findings indicate in general how silica wettability may be manipulated by electrolyte concentration.