Detailed Molecular Simulations Research Articles

Characterization of Cabot BP280 with argon and nitrogen adsorption at temperatures above and below the triple point – Energetic vs Structural heterogeneities

Abstract Wetting transitions on surfaces are a ubiquitous phenomenon in nature because the wettability depends on the balance between the adsorbate-adsorbent (which in turn depend on the surface topology), adsorbate-adsorbate interactions and temperature. To understand the separate contributions of these interactions in a wetting transition for a specific adsorbate-adsorbent pair, molecular simulation is an invaluable tool. Here we illustrate this with a detailed experimental and molecular simulation study of argon and nitrogen adsorption on Cabot BP280 at temperatures above and below their respective triple point temperatures. We report new adsorption isotherm data at 60 K and at 87 K and 77 K which confirm previous measurements on this adsorbent. These results were also used to calculate isosteric heats. Our TEM study shows that the surface of BP280 has a geometrically corrugated graphitic structure which is not as planar as highly graphitized thermal carbon black, such as Carbopack F. Simulations were carried out with two models: an energetic model built from strips of different adsorption strength, and a structural model consisting of crevices embedded in a graphite surface. Adsorption at temperatures below the triple point facilitates the probing of the fine details on the surface, enabling the discrimination between the energetic and structural molecular models, as proposed in this paper. The simulated isotherms and the isosteric heats, generated with the structural molecular models, agree very well with experimental data. Analyses of the microscopic mechanism of adsorption include local density distributions and snapshots of molecular configurations, and local order parameters were used to understand the packing of the adsorbate layer.

An analysis of the interactions between folic acid and aromatic guest molecules.

The formation of complexes between folate and therapeutic drug molecules is well known. In this work, we attempted to elucidate the role of the aromatic rings of folate and drug molecules in interactions between both of these molecules. A detailed molecular simulation study was carried out to explore the associative behavior of folic acid with phenylalanine and tyrosine, which show fluorescence emission following the excitation of these molecules at 257nm and 274nm, respectively. Therefore, studies of fluorescence emission from phenylalanine and tyrosine were performed in this work. The results of these studies indicated that folic acid associates with phenylalanine and tyrosine with binding constants ranging from 1.46×104 to 2.66×104M-1. X-ray diffraction studies suggested that folic acid self-assembly is maintained in the presence of associative interactions of the folic acid with guest molecules. These results demonstrate that the aromatic rings in the structures of the folic acid and the therapeutic drug play an important role in the encapsulation of guest molecules through folate self-assembly.

A detailed atomistic molecular simulation study on adsorption-based separation of CO2 using a porous coordination polymer.

Emission of CO2 is considered as one of the sources of global warming. Besides its currently inevitable production via several processes such as fuel consumption, it also exists in some other gaseous mixtures like biogas. Separation of carbon dioxide using solid adsorbents, for example porous coordination polymers and metal–organic frameworks, is an interesting active area of separation science. In particular, we performed detailed molecular simulations to investigate the response of a recently reported cobalt-based, pillared-layer, porous polymer on the CO2 separation from biogas, natural gas, and flue gas. The effect of the coordinated water molecules to the open metal sites on the corresponding properties was studied and revealed enhanced results even in comparison with HKUST-1. Additionally, our results provide insights on the role of –NO2 groups on the applications examined herein. Overall this study offers valuable insights about secondary building units of the examined materials which we expect to prove useful in the enhancement of carbon dioxide separation and capture.

PTHrP(12-48) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan.

Bone is a common site for metastasis in breast cancer patients and is associated with a series of complications that significantly compromise patient survival, partially due to the advanced stage of disease at the time of detection. Currently, no clinically-approved biomarkers can identify or predict the development of bone metastasis. We recently identified a unique peptide fragment of parathyroid hormone-related protein (PTHrP), PTHrP(12-48), as a validated serum biomarker in breast cancer patients that correlates with and predicts the presence of bone metastases. In this study, the biological activity and mode of action of PTHrP(12-48) was investigated. Sequence-based and structure-based bioinformatics techniques predicted that the PTHrP(12-48) fragment formed an alpha helical core followed by an unstructured region after residue 40 or 42. Thereafter, detailed structure alignment and molecular docking simulations predicted a lack of interaction between PTHrP(12-48) and the cognate PTH1 receptor (PTHR1). The in silico prediction was confirmed by the lack of PTHrP(12-48)-stimulated cAMP accumulation in PTHR1-expressing human SaOS2 cells. Using a specific human PTHrP(12-48) antibody that we developed, PTHrP(12-48) was immunolocalized in primary and bone metastatic human breast cancer cells, as well as within human osteoclasts (OCLs) in bone metastasis biopsies, with little or no localization in other resident bone or bone marrow cells. In vitro, PTHrP(12-48) was internalized into cultured primary human OCLs and their precursors within 60 min. Interestingly, PTHrP(12-48) treatment dose-dependently suppressed osteoclastogenesis, via the induction of apoptosis in both OCL precursors as well as in mature OCLs, as measured by the activation of cleaved caspase 3. Collectively, these data suggest that PTHrP(12-48) is a bioactive breast cancer-derived peptide that locally regulates the differentiation of hematopoietic cells and the activity of osteoclasts within the tumor-bone marrow microenvironment, perhaps to facilitate tumor control of bone. © 2017 American Society for Bone and Mineral Research.

Dependence of the Rate of LiF Ion-Pairing on the Description of Molecular Interaction.

We present an analysis of the dynamics of ion-pairing of lithium fluoride (LiF) in aqueous solvent using both detailed molecular simulation as well as reduced models within a generalized Langevin equation (GLE) framework. We explored the sensitivity of the ion-pairing phenomena to the details of descriptions of molecular interaction, comparing two empirical potentials to explicit quantum based density functional theory. We find quantitative differences in the potentials of mean force for ion-pairing as well as time dependent frictions that lead to variations in the rate constant and reactive flux correlation functions. These details reflect differences in solvent response to ion-pairing between different representations of molecular interaction and influence anharmonicity of the dynamic response. We find that the short-time anharmonic response is recovered with a GLE parametrization. Recovery of the details of long time response may require extensions to the reduced model. We show that the utility of using a reduced model leads to a straightforward application of variational transition state theory concepts to the condensed phase system. The significance of this is reflected in the analysis of committor distributions and the variation of planar hypersurfaces, leading to an improved understanding of factors that determine the rate of LiF ion-pairing.

Computational Modeling of bio-MOFs for CO2/CH4 separations

Bio-metal organic frameworks (Bio-MOFs), composed of biocompatible metal cations and linker molecules such as amino acids, nucleobases and sugars, are considered as promising candidates for gas storage and separation due to their permanent porosity, chemical functionality and structural tunability. In this study, detailed molecular simulations were performed to assess the potential of 10 different bio-MOFs in adsorption-based and membrane-based separation of CO2/CH4 mixtures. After showing the good agreement between experiments and molecular simulations for single-component adsorption isotherms of several gases in various bio-MOFs, adsorption selectivity and working capacity of these materials were predicted for CO2/CH4 separation. Membrane selectivity and gas permeability of bio-MOFs were computed considering flexibility of the structures in molecular simulations for the first time in the literature. Results showed that several bio-MOFs outperform widely studied MOFs and zeolites both in adsorption-based and membrane-based CO2/CH4 separations. Bio-MOF-1, bio-MOF-11 and bio-MOF-12 were identified as promising adsorbents and membranes for natural gas purification.

In silico affinity profiling of neuroactive polyphenols for post-traumatic calpain inactivation: a molecular docking and atomistic simulation sensitivity analysis.

Calcium-activated nonlysosomal neutral proteases, calpains, are believed to be early mediators of neuronal damage associated with neuron death and axonal degeneration after traumatic neural injuries. In this study, a library of biologically active small molecular weight calpain inhibitors was used for model validation and inhibition site recognition. Subsequently, two natural neuroactive polyphenols, curcumin and quercetin, were tested for their sensitivity and activity towards calpain’s proteolytic sequence and compared with the known calpain inhibitors via detailed molecular mechanics (MM), molecular dynamics (MD), and docking simulations. The MM and MD energy profiles (SJA6017 < AK275 < AK295 < PD151746 < quercetin < leupeptin < PD150606 < curcumin < ALLN < ALLM < MDL-28170 < calpeptin) and the docking analysis (AK275 < AK295 < PD151746 < ALLN < PD150606 < curcumin < leupeptin < quercetin < calpeptin < SJA6017 < MDL-28170 < ALLM) demonstrated that polyphenols conferred comparable calpain inhibition profiling. The modeling paradigm used in this study provides the first detailed account of corroboration of enzyme inhibition efficacy of calpain inhibitors and the respective calpain–calpain inhibitor molecular complexes’ energetic landscape and in addition stimulates the polyphenol bioactive paradigm for post-SCI intervention with implications reaching to experimental in vitro, in cyto, and in vivo studies.

Self-Consistent-Field Study of Adsorption and Desorption Kinetics of Polyethylene Melts on Graphite and Comparison with Atomistic Simulations

A method is formulated, based on combining self-consistent field theory with dynamically corrected transition state theory, for estimating the rates of adsorption and desorption of end-constrained chains (e.g., by cross-links or entanglements) from a polymer melt onto a solid substrate. This approach is tested on a polyethylene/graphite system, where the whole methodology is parametrized by atomistically detailed molecular simulations. For short-chain melts, which can still be addressed by molecular dynamics simulations with reasonable computational resources, the self-consistent field approach gives predictions of the adsorption and desorption rate constants which are gratifyingly close to molecular dynamics estimates.

Surface Ripples of Polymeric Nanofibers under Tension: The Crucial Role of Poisson’s Ratio

Molecular dynamics and finite element simulations are performed to study the phenomenon of surface rippling in polymeric nanofibers under tension. Each nanofiber is modeled as a core–shell system that resembles most relevant features extracted from detailed molecular simulations and experiments. Accordingly, our model nanofiber consists of a dense glassy core embedded in a less dense, more flexible, rubbery shell. Poisson’s ratios of the core and shell layers are assumed close to that of compressible and incompressible materials, respectively. Surface rippling of the nanofiber is found, via combined finite element analysis and continuum theory, to be governed by a “polarization” mechanism at the core–shell interphase regime that is ultimately induced by the mismatch between Poisson’s ratios while a mismatch between Young’s moduli seems to play a secondary role. Plastic deformation is a prerequisite for the formation of rippled surfaces, that evolve from initial imperfections, and grow in the presence of u...

The Structural Basis for Endotoxin-induced Allosteric Regulation of the Toll-like Receptor 4 (TLR4) Innate Immune Receptor

As part of the innate immune system, Toll-like receptor 4 (TLR4) recognizes bacterial cell surface lipopolysaccharide (LPS) by forming a complex with a lipid-binding co-receptor, MD-2. In the presence of agonist, TLR4·MD-2 dimerizes to form an active receptor complex, leading to initiation of intracellular inflammatory signals. TLR4 is of great biomedical interest, but its pharmacological manipulation is complicated because even subtle variations in the structure of LPS can profoundly impact the resultant immunological response. Here, we use atomically detailed molecular simulations to gain insights into the nature of the molecular signaling mechanism. We first demonstrate that MD-2 is extraordinarily flexible. The "clamshell-like" motions of its β-cup fold enable it to sensitively match the volume of its hydrophobic cavity to the size and shape of the bound lipid moiety. We show that MD-2 allosterically transmits this conformational plasticity, in a ligand-dependent manner, to a phenylalanine residue (Phe-126) at the cavity mouth previously implicated in TLR4 activation. Remarkably, within the receptor complex, we observe spontaneous transitions between active and inactive signaling states of Phe-126, and we confirm that Phe-126 is indeed the "molecular switch" in endotoxic signaling.

Cosolvent Effects on Protein Stability

Proteins are marginally stable, and the folding/unfolding equilibrium of proteins in aqueous solution can easily be altered by the addition of small organic molecules known as cosolvents. Cosolvents that shift the equilibrium toward the unfolded ensemble are termed denaturants, whereas those that favor the folded ensemble are known as protecting osmolytes. Urea is a widely used denaturant in protein folding studies, and the molecular mechanism of its action has been vigorously debated in the literature. Here we review recent experimental as well as computational studies that show an emerging consensus in this problem. Urea has been shown to denature proteins through a direct mechanism, by interacting favorably with the peptide backbone as well as the amino acid side chains. In contrast, the molecular mechanism by which the naturally occurring protecting osmolyte trimethylamine N-oxide (TMAO) stabilizes proteins is not clear. Recent studies have established the strong interaction of TMAO with water. Detailed molecular simulations, when used with force fields that incorporate these interactions, can provide insight into this problem. We present the development of a model for TMAO that is consistent with experimental observations and that provides physical insight into the role of cosolvent-cosolvent interaction in determining its preferential interaction with proteins.

Gas adsorption and diffusion in a highly CO2 selective metal–organic framework: molecular simulations

Grand canonical Monte Carlo and equilibrium molecular dynamics simulations were used to assess the performance of an rht-type metal–organic framework (MOF), Cu-TDPAT, in adsorption-based and membrane-based separation of CH4/H2, CO2/CH4 and CO2/H2 mixtures. Adsorption isotherms and self-diffusivities of pure gases and binary gas mixtures in Cu-TDPAT were computed using detailed molecular simulations. Several properties of Cu-TDPAT such as adsorption selectivity, working capacity, diffusion selectivity, gas permeability and permeation selectivity were computed and compared with well-known zeolites and MOFs. Results showed that Cu-TDPAT is a very promising adsorbent and membrane material especially for separation of CO2 and it can outperform traditional zeolites and MOFs such as DDR, MFI, CuBTC, IRMOF-1 in adsorption-based CO2/CH4 and CO2/H2 separations.

Force Field Development for Actinyl Ions via Quantum Mechanical Calculations: An Approach to Account for Many Body Solvation Effects

Advances in computational algorithms and methodologies make it possible to use highly accurate quantum mechanical calculations to develop force fields (pair-wise additive intermolecular potentials) for condensed phase simulations. Despite these advances, this approach faces numerous hurdles for the case of actinyl ions, AcO2(n+) (high-oxidation-state actinide dioxo cations), mainly due to the complex electronic structure resulting from an interplay of s, p, d, and f valence orbitals. Traditional methods use a pair of molecules (“dimer”) to generate a potential energy surface (PES) for force field parametrization based on the assumption that many body polarization effects are negligible. We show that this is a poor approximation for aqueous phase uranyl ions and present an alternative approach for the development of actinyl ion force fields that includes important many body solvation effects. Force fields are developed for the UO2(2+) ion with the SPC/Fw, TIP3P, TIP4P, and TIP5P water models and are validated by carrying out detailed molecular simulations on the uranyl aqua ion, one of the most characterized actinide systems. It is shown that the force fields faithfully reproduce available experimental structural data and hydration free energies. Failure to account for solvation effects when generating PES leads to overbinding between UO2(2+) and water, resulting in incorrect hydration free energies and coordination numbers. A detailed analysis of arrangement of water molecules in the first and second solvation shell of UO2(2+) is presented. The use of a simple functional form involving the sum of Lennard-Jones + Coulomb potentials makes the new force field compatible with a large number of available molecular simulation engines and common force fields.

Computational screening of metal organic frameworks for mixed matrix membrane applications

In this study, detailed molecular simulations were used to examine the challenge of selecting metal organic frameworks (MOFs) as filler particles in high performance mixed matrix membranes (MMMs) for separation of H2 from CH4. The predictions of theoretical permeation models for gas permeability were compared with the experimental data of IRMOF-1/Matrimid, CuBTC/PSF, CuBTC/PDMS and Cu-BPY-HFS/Matrimid MMMs. The good agreement between experiments and our theoretical predictions motivated us to estimate performances of one hundred and nineteen new MOF-based MMMs, composed of seventeen different MOFs and seven different polymers. We identified several MOF-based MMMs exhibiting very high H2 selectivity and H2 permeability relative to pure polymer membranes. Finally, we discussed the ways of selecting appropriate MOFs as filler particles for a given polymer matrix which will result in MMMs with promising properties for H2 separations.

Materials for organic photovoltaics: insights from detailed structural models and molecular simulations

This paper contains a brief discussion of the role of detailed structural and computational studies, within the general field of organic photovoltaics. We review some of our recent work on poly(3-butylthiophene) (P3BT) and on [6,6]phenyl-C61-butyric acid methyl ester (PCBM). The first is a prototypical hole-transporting material, whose crystal forms I.’ and II were solved by us through the combined use of powder Xray diffraction, electron diffraction and molecular modelling. PCBM is a widely used fullerene derivative with electron-transporting properties. It has a rich polymorphism, which to date remains largely unexplored. Our molecular dynamics simulations have revealed interesting features of its solid-state organization, including that in the amorphous phase.

Improving the equilibrium performance of active carbons for separation processes by co-adsorption with low pressure solvent: application to carbon capture

The equilibrium performance of a novel gas separation process described quite recently (Sweatman in Chem. Eng. Sci. 65:3907, 2010) called ‘pressure-swing wetting layer absorption’ here is investigated by means of molecular Monte-Carlo simulation. This process is very similar to pressure-swing adsorption except that solvent, in the form of low pressure vapour, is added to the gas to be separated in order to improve equilibrium performance. Earlier work, based on relatively simple density functional theory models, suggests that this process could be significantly more efficient than the analogous pressure-swing adsorption process when tetrahydrofuran (THF) is used as the solvent, although this conclusion is based only on equilibrium behaviour and does not take into account the effect of any dynamical processes. The aim of this work is to provide more detailed molecular simulation results to help understand this behaviour and guide experiments towards suitable solvents and conditions so that the process can experimentally tested. It is found that using acetonitrile as the solvent could be over nine times more effective than THF, which was modelled in previous work, for the particular carbon capture application studied here. These simulation results also demonstrate that, due to the effect of confinement on fluid structure, bulk solubility data cannot be used to reliably predict equilibrium performance in this context, and that the equilibrium performance is especially enhanced for pores that exhibit a bilayer phase transition.

The Contribution of Interchain Salt Bridges to Triple-Helical Stability in Collagen

Studies on collagen and collagen-like peptides suggest that triple-helical stability can vary along the amino acid chain. In this regard, it has been shown that lysine residues in the Y position and acidic residues in the X′ position of (GPO)3GXYGX′Y′(GPO)3 peptides lead to triple-helical structures with melting temperatures similar to (GPO)8 (where O is hydroxyproline), which is generally regarded as the most stable collagen-like sequence of this length. This enhanced stability has been attributed to the formation of salt bridges between adjacent collagen chains. In this study, we explore the relationship between interchain salt bridge formation and triple-helical stability using detailed molecular simulations. Although our results confirm that salt bridges promote triple-helical stability, we find that not all salt bridges are created equal. In particular, lysine-glutamate salt bridges are most stabilizing when formed between residues in the middle strand (B) and the trailing strand (C), whereas lysine-aspartate salt bridges are most stabilizing when formed between residues in the leading (A) and middle (B) strand—the latter observation being consistent with recent NMR data on a heterotrimeric model peptide. Overall, we believe these data clarify the role of salt bridges in modulating triple-helical stability and can be used to guide the design of collagen-like peptides that have specific interchain interactions.

Physical Basis of Metal-Binding Specificity in Escherichia coli NikR

In Escherichia coli and other bacteria, nickel uptake is regulated by the transcription factor NikR. Nickel binding at high-affinity sites in E. coli NikR (EcNikR) facilitates EcNikR binding to the nik operon, where it then suppresses transcription of genes encoding the nickel uptake transporter, NikABCDE. A structure of the EcNikR-DNA complex suggests that a second metal-binding site is also present when NikR binds to the nik operon. Moreover, this co-crystal structure raises the question of what metal occupies the second site under physiological conditions: K(+), which is present in the crystal structure, or Ni(2+), which has been proposed to bind to low- as well as high-affinity sites on EcNikR. To determine which ion is preferred at the second metal-binding site and the physical basis for any preference of one ion over another in both the second metal-binding site and the high-affinity sites, we conducted a series of detailed molecular simulations on the EcNikR structure. Simulations that place Ni(2+) at high-affinity sites lead to stable trajectories with realistic ion-ligand distances and geometries, while simulations that place K(+) at these sites lead to conformational changes in the protein that are likely unfavorable for ion binding. By contrast, simulations on the second metal site in the EcNikR-DNA complex lead to stable trajectories with realistic geometries regardless of whether K(+) or Ni(2+) occupies this site. Electrostatic binding free energy calculations, however, suggest that EcNikR binding to DNA is more favorable when the second metal-binding site contains K(+). An analysis of the energetic contributions to the electrostatic binding free energy suggests that, while the interaction between EcNikR and DNA is more favorable when the second site contains Ni(2+), the large desolvation penalty associated with moving Ni(2+) from solution to the relatively buried second site offsets this favorable interaction term. Additional free energy simulations that account for both electrostatic and non-electrostatic effects argue that EcNikR binding to DNA is most favorable when the second site contains a monovalent ion the size of K(+). Taken together, these data suggest that the EcNikR structure is most stable when Ni(2+) occupies high-affinity sites and that EcNikR binding to DNA is more favorable when the second site contains K(+).

The folding mechanism of collagen‐like model peptides explored through detailed molecular simulations

Collagen has a unique folding mechanism that begins with the formation of a triple-helical structure near its C terminus followed by propagation of this structure to the N terminus. To elucidate factors that affect the folding of collagen, we explored the folding pathway of collagen-like model peptides using detailed molecular simulations with explicit solvent. Using biased molecular dynamics we examined the latter stages of folding of a peptide model of native collagen, (Pro-Hyp-Gly)10, and a peptide that models a Gly --> Ser mutation found in several forms of osteogenesis imperfecta, (Pro-Hyp-Gly)3-Pro-Hyp-Ser-(Pro-Hyp-Gly)6. Starting from an unfolded state that contains a C-terminal nucleated trimer, (Pro-Hyp-Gly)10 folds to a structure where two of the three chains associate through water-mediated hydrogen bonds and the third is relatively separated from this dimer. Calculated free-energy profiles for folding from this intermediate to the final triple-helical structure suggest that further folding occurs at a rate of approximately one Pro-Hyp-Gly triplet per msec. In contrast, after 6 nsec of biased dynamics, the region N-terminal to the Ser residue in (Pro-Hyp-Gly)3-Pro-Hyp-Ser-(Pro-Hyp-Gly)6 folds to a structure where the three chains form close contacts near the N terminus, away from the mutation site. Further folding to an ideal triple-helical structure at the site of the mutation is unfavorable as the free energy of a triple-helical conformation at this position is more than 20 kcal/mol higher than that of a structure with unassociated chains. These data provide insights into the folding pathway of native collagen and the events underlying the formation of misfolded structures.

Detailed molecular simulations to investigate multicomponent diffusion models

AbstractThe theoretical treatment of multicomponent diffusion is complicated by the generally unknown dependence of diffusivities on the local concentration of species. As pointed out by Nauman and Savoca in 2001, the standard treatment uses an n‐1 by n‐1 matrix of diffusion coefficients for an n‐component system and can give anomalous and non‐physical results when there is no dominant component and when the various components have significantly different diffusivities. Although theoretically resolved by postulating diffusivities with suitable concentration dependence, there has been no practical resolution of this problem short of unrealistic, exhaustive experimentation. Nauman and Savoca proposed two models for multicomponent diffusion that produce only physically possible results, but they were unable to suggest which model was better. This article reports on molecular dynamic experiments that were designed to differentiate between the models. Specifically studied were ternary, liquid mixtures of ethane, octane, and hexadecane. It was found that the proportional flux model agrees with the molecular simulations. No cross‐diffusion was observed in agreement with this model and in contrast to the alternative, pair‐wise flux model. The proportional flux model is easy to implement and requires a minimum of data, although detailed, compositional dependent diffusion coefficients can be incorporated into the model when such data are available. © 2005 American Institute of Chemical Engineers AIChE J, 2006