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Skin barrier function is localized in its outermost layer, the stratum corneum (SC), which is comprised of corneocyte cells embedded in an extracellular lipid matrix containing ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs). The unique structure and composition of this lipid matrix are important for skin barrier function. In this study, experiments and molecular dynamics simulation were combined to investigate the structural properties and phase behavior of mixtures containing nonhydroxy sphingosine CER (CER NS), CHOL, and FFA. X-ray scattering for mixtures with varying CHOL levels revealed the presence of the 5.4 nm short periodicity phase in the presence of CHOL. Bilayers in coarse-grained multilayer simulations of the same compositions contained domains with thicknesses of approximately 5.3 and 5.8 nm that are associated with elevated levels, respectively, of CER sphingosine chains with CHOL, and CER acyl chains with FFA chains. The prevalence of the thicker domain increased with decreasing CHOL content. This might correspond to a phase with ∼5.8 nm spacing observed by x-rays (other details unknown) in mixtures with lower CHOL content. Scissoring and stretching frequencies from Fourier transform infrared spectroscopy (FTIR) also indicate interaction between FFA and CER acyl chains and little interaction between CER acyl and CER sphingosine chains, which requires CER molecules to adopt a predominantly extended conformation. In the simulated systems, neighbor preferences of extended CER chains align more closely with the FTIR observations than those of CERs with hairpin ceramide chains. Both FTIR and atomistic simulations of reverse mapped multilayer membranes detect a hexagonal to fluid phase transition between 65 and 80°C. These results demonstrate the utility of a collaborative experimental and simulation effort in gaining a more comprehensive understanding of SC lipid membranes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The lipids located in the outermost layer of the skin, the stratum corneum (SC), play a crucial role in maintaining the skin barrier function. The primary components of the SC lipid matrix are ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs). They form two crystalline lamellar phases: the long periodicity phase (LPP) and the short periodicity phase (SPP). In inflammatory skin conditions like atopic dermatitis and psoriasis, there are changes in the SC CER composition, such as an increased concentration of a sphingosine-based CER (CER NS) and a reduced concentration of a phytosphingosine-based CER (CER NP). In the present study, a lipid model was created exclusively forming the SPP, to examine whether alterations in the CER NS:CER NP molar ratio would affect the lipid organization. Experimental data were combined with molecular dynamics simulations of lipid models containing CER NS:CER NP at ratios of 1:2 (mimicking a healthy SC ratio) and 2:1 (observed in inflammatory skin diseases), mixed with CHOL and lignoceric acid as the FFA. The experimental findings show that the acyl chains of CER NS and CER NP and the FFA are in close proximity within the SPP unit cell, indicating that CER NS and CER NP adopt a linear conformation, similarly as observed for the LPP. Both the experiments and simulations indicate that the lamellar organization is the same for the two CER NS:CER NP ratios while the SPP NS:NP 1:2 model had a slightly denser hydrogen bonding network than the SPP NS:NP 2:1 model. The simulations show that this might be attributed to intermolecular hydrogen bonding with the additional hydroxide group on the headgroup of CER NP compared with CER NS.

We have developed a multi-input E( n ) equivariant graph convolution-based model designed for the prediction of chemical properties that result from the interaction of heterogeneous molecular structures. By incorporating spatial features and constraining the functions learned from these features to be equivariant to E( n ) symmetries, the interactional-equivariant graph neural network (IEGNN) can efficiently learn from the 3D structure of multiple molecules. To verify the IEGNN's capability to learn interactional properties, we tested the model's performance on three molecular data sets, two of which are curated in this study and made publicly available for future interactional model benchmarking. To enable the loading of these data sets, an open-source data structure based on the PyTorch Geometric library for batch loading multigraph data points is also created. Finally, the IEGNN's performance on a data set consisting of an unknown interactional relationship (the frictional properties resulting between monolayers with variable composition) is examined. The IEGNN model developed was found to have the lowest mean absolute percent error for the predicted tribological properties of four of the six data sets when compared to previous methods.

Claudin 18.2 (CLDN18.2), the dominant isoform of CLDN18 in gastric tissues, is a highly specific tight junction protein of the gastric mucosa with variably retained expressions in gastric and gastroesophageal junction cancers. Additionally, CLDN18.2-targeted treatment with zolbetuximab, in combination with chemotherapy, has recently been assessed in 2 phase-III studies of patients with HER2-negative, locally advanced, unresectable, or metastatic gastric or gastroesophageal junction adenocarcinoma. These trials used the investigational VENTANA CLDN18 (43-14A) RxDx immunohistochemistry (IHC) assay on the Ventana BenchMark platform to identify patients eligible for CLDN18.2-targeted treatment. We report the findings of a global ring study evaluating the analytical comparability of concordance of the results of 3 CLDN18 antibodies (Ventana, LSBio, and Novus) stained on 3 IHC-staining platforms (Ventana, Dako, and Leica). A tissue microarray (TMA), comprising 15 gastric cancer cases, was stained by 27 laboratories across 11 countries. Each laboratory stained the TMAs using at least 2 of the 3 evaluated CLDN18 antibodies. Stained TMAs were assessed and scored using an agreed IHC-scoring algorithm, and the results were collated for statistical analysis. The data confirmed a high level of concordance for the VENTANA CLDN18 (43-14A; Ventana platform only) and LSBio antibodies on both the Dako and Leica platforms, with accuracy, precision, sensitivity, and specificity rates all reaching a minimum acceptable ≥85% threshold and good-to-excellent levels of concordance as measured by Cohen's kappa coefficient. The Novus antibody showed the highest level of variability against the reference central laboratory results for the same antibody/platform combinations. It also failed to meet the threshold for accuracy and sensitivity when used on either the Dako or Leica platform. These results demonstrated the reliability of IHC testing for CLDN18 expression in gastric tumor samples when using commercially available platforms with an appropriate methodology and primary antibody selection., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The barrier function of the skin is primarily located in the stratum corneum (SC), the outermost layer of the skin. The SC is composed of dead cells with highly organized lipid lamellae in the intercellular space. As the lipid matrix forms the only continuous pathway, the lipids play an important role in the permeation of compounds through the SC. The main lipid classes are ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs). Analysis of the SC lipid matrix is of crucial importance in understanding the skin barrier function, not only in healthy skin, but also in inflammatory skin diseases with an impaired skin barrier. In this review we provide i) a historical overview of the steps undertaken to obtain information on the lipid composition and organization in SC of healthy skin and inflammatory skin diseases, ii) information on the role CERs, CHOL and FFAs play in the lipid phase behavior of very complex lipid model systems and how this knowledge can be used to understand the deviation in lipid phase behavior in inflammatory skin diseases, iii) knowledge on the role of both, CER subclasses and chain length distribution, on lipid organization and lipid membrane permeability in complex and simple model systems with synthetic CERs, CHOL and FFAs, iv) similarity in lipid phase behavior in SC of different species and complex model systems, and vi) future directions in modulating lipid composition that is expected to improve the skin barrier in inflammatory skin diseases., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

MoSDeF-GOMC is a python interface for the Monte Carlo software GOMC to the Molecular Simulation Design Framework (MoSDeF) ecosystem. MoSDeF-GOMC automates the process of generating initial coordinates, assigning force field parameters, and writing coordinate (PDB), connectivity (PSF), force field parameter, and simulation control files. The software lowers entry barriers for novice users while allowing advanced users to create complex workflows that encapsulate simulation setup, execution, and data analysis in a single script. All relevant simulation parameters are encoded within the workflow, ensuring reproducible simulations. MoSDeF-GOMC's capabilities are illustrated through a number of examples, including prediction of the adsorption isotherm for CO 2 in IRMOF-1, free energies of hydration for neon and radon over a broad temperature range, and the vapor-liquid coexistence curve of a four-component surrogate for the jet fuel S-8. The MoSDeF-GOMC software is available on GitHub at https://github.com/GOMC-WSU/MoSDeF-GOMC.

Skin's effectiveness as a barrier to permeation of water and other chemicals rests almost entirely in the outermost layer of the epidermis, the stratum corneum (SC), which consists of layers of corneocytes surrounded by highly organized lipid lamellae. As the only continuous path through the SC, transdermal permeation necessarily involves diffusion through these lipid layers. The role of the SC as a protective barrier is supported by its exceptional lipid composition consisting of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs) and the complete absence of phospholipids, which are present in most biological membranes. Molecular simulation, which provides molecular level detail of lipid configurations that can be connected with barrier function, has become a popular tool for studying SC lipid systems. We review this ever-increasing body of literature with the goals of (1) enabling the experimental skin community to understand, interpret and use the information generated from the simulations, (2) providing simulation experts with a solid background in the chemistry of SC lipids including the composition, structure and organization, and barrier function, and (3) presenting a state of the art picture of the field of SC lipid simulations, highlighting the difficulties and best practices for studying these systems, to encourage the generation of robust reproducible studies in the future. This review describes molecular simulation methodology and then critically examines results derived from simulations using atomistic and then coarse-grained models., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Molecular dynamics simulations of mixtures of the ceramide nonhydroxy-sphingosine (NS), cholesterol, and a free fatty acid are performed to gain molecular-level understanding of the structure of the lipids found in the stratum corneum layer of skin. A new coarse-grained force field for cholesterol was developed using the multistate iterative Boltzmann inversion (MS-IBI) method. The coarse-grained cholesterol force field is compatible with previously developed coarse-grained force fields for ceramide NS, free fatty acids, and water and validated against atomistic simulations of these lipids using the CHARMM force field. Self-assembly simulations of multilayer structures using these coarse-grained force fields are performed, revealing that a large fraction of the ceramides adopt extended conformations, which cannot occur in the single bilayer in water structures typically studied using molecular simulation. Cholesterol fluidizes the membrane by promoting packing defects, and an increase in cholesterol content is found to reduce the bilayer thickness due to an increase in interdigitation of the C 24 lipid tails, consistent with experimental observations. Using a reverse-mapping procedure, a self-assembled coarse-grained multilayer system is used to construct an equivalent structure with atomistic resolution. Simulations of this atomistic structure are found to closely agree with experimentally derived neutron scattering length density profiles. Significant interlayer hydrogen bonding is observed in the inner layers of the atomistic multilayer structure that are not found in the outer layers in contact with water or in equivalent bilayer structures. This work highlights the importance of simulating multilayer structures, as compared to the more commonly studied bilayer systems, to enable more appropriate comparisons with multilayer experimental membranes. These results also provide validation of the efficacy of the MS-IBI derived coarse-grained force fields and the framework for multiscale simulation.

Monolayer films have shown promise as a lubricating layer to reduce friction and wear of mechanical devices with separations on the nanoscale. These films have a vast design space with many tunable properties that can affect their tribological effectiveness. For example, terminal group chemistry, film composition, and backbone chemistry can all lead to films with significantly different tribological properties. This design space, however, is very difficult to explore without a combinatorial approach and an automatable, reproducible, and extensible workflow to screen for promising candidate films. Using the Molecular Simulation Design Framework (MoSDeF), a combinatorial screening study was performed to explore 9747 unique monolayer films (116 964 total simulations) and a machine learning (ML) model using a random forest regressor, an ensemble learning technique, to explore the role of terminal group chemistry and its effect on tribological effectiveness. The most promising films were found to contain small terminal groups such as cyano and ethylene. The ML model was subsequently applied to screen terminal group candidates identified from the ChEMBL small molecule library. Approximately 193 131 unique film candidates were screened with approximately a five order of magnitude speed-up in analysis compared to simulation alone. The ML model was thus able to be used as a predictive tool to greatly speed up the initial screening of promising candidate films for future simulation studies, suggesting that computational screening in combination with ML can greatly increase the throughput in combinatorial approaches to generate in silico data and then train ML models in a controlled, self-consistent fashion.

In this work, molecular dynamics simulations are used to examine the self-assembly of anisotropically coated "patchy" nanoparticles. Specifically, we use a coarse-grained model to examine silica nanoparticles coated with alkane chains, where the poles of the grafted nanoparticle are bare, resulting in strongly attractive patches. Through a systematic screening process, the patchy nanoparticles are found to form dispersed, string-like, and aggregated phases, dependent on the combination of alkane chain length, coating chain density, and the fractional coated surface area. Correlation analysis is used to identify the ability of various particle descriptors to predict bulk phase behavior from more computationally efficient single grafted nanoparticle simulations and demonstrates that the solvent-accessible surface area of the nanoparticle core is a key predictor of bulk phase behavior. The results of this work enhance our knowledge of the phase space of patchy nanoparticles and provide a powerful approach for future screening of these materials.

The structural properties of two- and three-component gel-phase bilayers were studied using molecular dynamics simulations. The bilayers contain distearoylphosphatidylcholine (DSPC) phospholipids mixed with alcohols and/or fatty acids of varying tail lengths, with carbon chain lengths of 12, 16, and 24 studied. Changes in both headgroup chemistry and tail length are found to affect the balance between steric repulsion and van der Waals attraction within the bilayers, manifesting in different bilayer structural properties. Lipid components are found to be located at different depths within the bilayer depending on both chain length and headgroup chemistry. The highest bilayer ordering and lowest area per tail are found in systems with medium-length tails. While longer tails can enhance van der Waals attractions, the increased tail-length asymmetry is found to induce disorder and reduce tail packing. Bulkier headgroups further increase steric repulsion, as reflected in increased component offsets and reduced tail packing. These findings help explain how bilayer composition affects the structure of gel-phase bilayers.

We demonstrate how the recently developed Python-based Molecular Simulation and Design Framework (MoSDeF) can be used to perform molecular dynamics screening of functionalized monolayer films, focusing on tribological effectiveness. MoSDeF is an open-source package that allows for the programmatic construction and parametrization of soft matter systems and enables TRUE (transferable, reproducible, usable by others, and extensible) simulations. The MoSDeF-enabled screening identifies several film chemistries that simultaneously show low coefficients of friction and adhesion. We additionally develop a Python library that utilizes the RDKit cheminformatics library and the scikit-learn machine learning library that allows for the development of predictive models for the tribology of functionalized monolayer films and use this model to extract information on terminal group characteristics that most influence tribology, based on the screening data.

Using molecular dynamics simulations, it is demonstrated that a partial coating of single-stranded DNA (ssDNA) reduces the penetration depth of a graphene nanoflake (GNF) into a phospholipid bilayer by attenuating the hydrophobic force that drives the penetration. As the GNF penetrates the bilayer, the ssDNA remains adsorbed to the GNF outside of the bilayer where it shields the graphene from the surrounding water. The penetration depth is found to be controlled by the amount of ssDNA coating the GNF, with a sparser coating resulting in a deeper penetration since the ssDNA shields less of the GNF surface. As the coating density is increased, the likelihood of the GNF entering the bilayer is reduced where it instead tends to lie flat on the bilayer surface with the sugar phosphate backbone of ssDNA interacting with the hydrophilic lipid head groups. While no bilayer disruption is observed for a partially inserted ssDNA-coated GNF, a larger, bare, partially inserted GNF is found to preferentially extract phospholipids from the bilayer, offering further evidence of lipid extraction as a main cytotoxicity mechanism of GNFs. Therefore, a coating of ssDNA may reduce the cytotoxicity of GNFs by shielding the unfavorable graphene-water interaction, thus preventing graphene penetration and lipid extraction.

Despite the ubiquity of nanoparticles in modern materials research, computational scientists are often forced to choose between simulations featuring detailed models of only a few nanoparticles or simplified models with many nanoparticles. Herein, we present a coarse-grained model for amorphous silica nanoparticles with parameters derived via potential matching to atomistic nanoparticle data, thus enabling large-scale simulations of realistic models of silica nanoparticles. Interaction parameters are optimized to match a range of nanoparticle diameters in order to increase transferability with nanoparticle size. Analytical functions are determined such that interaction parameters can be obtained for nanoparticles with arbitrary coarse-grained fidelity. The procedure is shown to be extensible to the derivation of cross-interaction parameters between coarse-grained nanoparticles and other moieties and validated for systems of grafted nanoparticles. The optimization procedure used is available as an open-source Python package and should be readily extensible to models of non-silica nanoparticles.

Cross-linked chemisorbed n -alkylsilane (CH 3 (CH 2 ) n -1 Si(OH) 3 ) monolayers on amorphous silica surfaces have been studied and their structural properties and frictional performance were compared to those of equivalent monolayers without cross-linkages. The simulations isolated for the first time the effects of both siloxane cross-linkages and the fraction of chains chemisorbed to the surface, providing insight into a longstanding fundamental question in the literature regarding molecular-level structure. The results demonstrate that both cross-linkages and the fraction of chemisorbed chains affect monolayer structure in small but measurable ways, particularly for monolayers constructed from short chains; however, these changes do not appear to have a significant impact on frictional performance.

The permeability of multicomponent phospholipid bilayers in the gel phase is investigated via molecular dynamics simulation. The physical role of the different molecules is probed by comparing multiple mixed-component bilayers containing distearylphosphatidylcholine (DSPC) with varying amounts of either the emollient isostearyl isostearate or long-chain alcohol (dodecanol, octadecanol, or tetracosanol) molecules. Permeability is found to depend on both the tail packing density and hydrogen bonding between lipid headgroups and water. Whereas the addition of emollient or alcohol molecules to a gel-phase DSPC bilayer can increase the tail packing density, it also disturbed the hydrogen-bonding network, which in turn can increase interfacial water dynamics. These phenomena have opposing effects on bilayer permeability, which is found to depend on the balance between enhanced tail packing and decreased hydrogen bonding.

The lipid matrix of the stratum corneum (SC) layer of skin is essential for human survival; it acts as a barrier to prevent rapid dehydration while keeping potentially hazardous material outside the body. While the composition of the SC lipid matrix is known, the molecular-level details of its organization are difficult to infer experimentally, hindering the discovery of structure-property relationships. To this end, molecular dynamics simulations, which give molecular-level resolution, have begun to play an increasingly important role in understanding these relationships. However, most simulation studies of SC lipids have focused on preassembled bilayer configurations, which, owing to the slow dynamics of the lipids, may influence the final structure and hence the calculated properties. Self-assembled structures would avoid this dependence on the initial configuration, however, the size and length scales involved make self-assembly impractical to study with atomistic models. Here, we report on the development of coarse-grained models of SC lipids designed to study self-assembly. Building on previous work, we present the interactions between the headgroups of ceramide and free fatty acid developed using the multistate iterative Boltzmann inversion method. Validation of the new interactions is performed with simulations of preassembled bilayers and good agreement between the atomistic and coarse-grained models is found for structural properties. The self-assembly of mixtures of ceramide and free fatty acid is investigated and both bilayer and multilayer structures are found to form. This work therefore represents a necessary step in studying SC lipid systems on multiple time and length scales., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Lipid bilayers composed of non-hydroxy sphingosine ceramide (CER NS), cholesterol (CHOL), and free fatty acids (FFAs), which are components of the human skin barrier, are studied via molecular dynamics simulations. Since mixtures of these lipids exist in dense gel phases with little molecular mobility at physiological conditions, care must be taken to ensure that the simulations become decorrelated from the initial conditions. Thus, we propose and validate an equilibration protocol based on simulated tempering, in which the simulation takes a random walk through temperature space, allowing the system to break out of metastable configurations and hence become decorrelated from its initial configuration. After validating the equilibration protocol, which we refer to as random-walk molecular dynamics, the effects of the lipid composition and ceramide tail length on bilayer properties are studied. Systems containing pure CER NS, CER NS + CHOL, and CER NS + CHOL + FFA, with the CER NS fatty acid tail length varied within each CER NS-CHOL-FFA composition, are simulated. The bilayer thickness is found to depend on the structure of the center of the bilayer, which arises as a result of the tail-length asymmetry between the lipids studied. The hydrogen bonding between the lipid headgroups and with water is found to change with the overall lipid composition, but is mostly independent of the CER fatty acid tail length. Subtle differences in the lateral packing of the lipid tails are also found as a function of CER tail length. Overall, these results provide insight into the experimentally observed trend of altered barrier properties in skin systems where there are more CERs with shorter tails present., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Chemisorbed monolayer films are known to possess favorable characteristics for nanoscale lubrication of micro- and nanoelectromechanical systems (MEMS/NEMS). Prior studies have shown that the friction observed for monolayer-coated surfaces features a strong dependence on the geometry of contact. Specifically, tip-like geometries have been shown to penetrate into monolayer films, inducing defects in the monolayer chains and leading to plowing mechanisms during shear, which result in higher coefficients of friction (COF) than those observed for planar geometries. In this work, we use molecular dynamics simulations to examine the tribology of model silica single-asperity contacts under shear with monolayer-coated substrates featuring various film densities. It is observed that lower monolayer densities lead to reduced COFs, in contrast to results for planar systems where COF is found to be nearly independent of monolayer density. This is attributed to a liquid-like response to shear, whereby fewer defects are imparted in monolayer chains from the asperity, and chains are easily displaced by the tip as a result of the higher free volume. This transition in the mechanism of molecular plowing suggests that liquid-like films should provide favorable lubrication at single-asperity contacts.

A force field for perfluoropolyethers (PFPEs) based on the general optimized potentials for liquid simulations all-atom (OPLS-AA) force field has been derived in conjunction with experiments and ab initio quantum mechanical calculations. Vapor pressures and densities of two liquid PFPEs, perfluorodiglyme (CF 3 -O-(CF 2 -CF 2 -O) 2 -CF 3 ) and perfluorotriglyme (CF 3 -O-(CF 2 -CF 2 -O) 3 -CF 3 ), have been measured experimentally to validate the force field and increase our understanding of the physical properties of PFPEs. Force field parameters build upon those for related molecules (e.g., ethers and perfluoroalkanes) in the OPLS-AA force field, with new parameters introduced for interactions specific to PFPEs. Molecular dynamics simulations using the new force field demonstrate excellent agreement with ab initio calculations at the RHF/6-31G* level for gas-phase torsional energies (<0.5 kcal mol -1 error) and molecular structures for several PFPEs, and also accurately reproduce experimentally determined densities (<0.02 g cm -3 error) and enthalpies of vaporization derived from experimental vapor pressures (<0.3 kcal mol -1 ). Additional comparisons between experiment and simulation show that polyethers demonstrate a significant decrease in enthalpy of vaporization upon fluorination unlike related molecules (e.g., alkanes and alcohols). Simulation suggests this phenomenon is a result of reduced cohesion in liquid PFPEs due to a reduction in localized associations between backbone oxygen atoms and neighboring molecules.

The structural properties of two-component gel-phase bilayers of distearylphosphatidylcholine (DSPC) and alcohol molecules with different compositions and chain lengths (12-24 carbons long) are studied via molecular dynamics simulations. Several bilayer properties, including area per lipid, tilt angle, chain interdigitation, and headgroup offset, are studied for each system and compared, revealing important structural implications depending upon headgroup size and chain length. While tail tilt is the primary mechanism for single-component bilayers to balance tail attraction and headgroup repulsion, our results demonstrate that the lipid mixtures studied adjust this balance via an offset between the depths of the different molecular species in the bilayer; this behavior is found to depend both on composition and on the length of alcohol molecules relative to the length of DSPC tails. It is shown that the structural properties of bilayers with asymmetric tail lengths depend strongly on the bilayer composition, while the composition has less influence on mixed-component bilayers with nearly symmetric tail lengths. These findings are explained on the basis of the interdigitation between bilayer leaflets and how interdigitation is related to other structural properties.

Ceramide (CER)-based biological membranes are used both experimentally and in simulations as simplified model systems of the skin barrier. Molecular dynamics studies have generally focused on simulating preassembled structures using atomistically detailed models of CERs, which limit the system sizes and time scales that can practically be probed, rendering them ineffective for studying particular phenomena, including self-assembly into bilayer and lamellar superstructures. Here, we report on the development of a coarse-grained (CG) model for CER NS, the most abundant CER in human stratum corneum. Multistate iterative Boltzmann inversion is used to derive the intermolecular pair potentials, resulting in a force field that is applicable over a range of state points and suitable for studying ceramide self-assembly. The chosen CG mapping, which includes explicit interaction sites for hydroxyl groups, captures the directional nature of hydrogen bonding and allows for accurate predictions of several key structural properties of CER NS bilayers. Simulated wetting experiments allow the hydrophobicity of CG beads to be accurately tuned to match atomistic wetting behavior, which affects the whole system, since inaccurate hydrophobic character is found to unphysically alter the lipid packing in hydrated lamellar states. We find that CER NS can self-assemble into multilamellar structures, enabling the study of lipid systems more representative of the multilamellar lipid structures present in the skin barrier. The coarse-grained force field derived herein represents an important step in using molecular dynamics to study the human skin barrier, which gives a resolution not available through experiment alone.

Single- and multicomponent lipid bilayers of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC), isostearyl isostearate, and heptadecanoyl heptadecanoate in the gel phase are studied via molecular dynamics simulations. It is shown that the structural properties of multicomponent bilayers can deviate strongly from the structures of their single-component counterparts. Specifically, the lipid mixtures are shown to adopt a compact packing by offsetting the positioning depths at which different lipid species are located in the bilayer. This packing mechanism affects the area per lipid, the bilayer height, and the chain tilt angles and has important consequences for other bilayer properties, such as interfacial hydrogen bonding and bilayer permeability. In particular, the simulations suggest that bilayers containing isostearyl isostearate or heptadecanoyl heptadecanoate are less permeable than pure 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine or DSPC bilayers. Furthermore, hydrogen-bond analysis shows that the residence times of lipid-water hydrogen bonds depend strongly on the bilayer composition, with longer residence times for bilayers that have a higher DSPC content. The findings illustrate and explain the fundamental differences between the properties of single- and multicomponent bilayers., (Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Chemisorbed alkylsilane monolayer coatings have been shown to possess favorable lubrication properties; however, film degradation prevents the widespread use of these materials as lubricants in micro- and nanoelectromechanical systems (MEMS/NEMS). In this work, molecular dynamics (MD) simulations are used to provide insight into the conditions that promote the degradation and wear of these materials. This is achieved through removal of interfacial chain-substrate bonds during shear and the examination of the mobility of the resulting free, unbound chains. Specific focus is given to the effects of surface morphology, which has been shown previously to strongly influence frictional forces in monolayer systems. In-plane order of chain attachments is shown to lead to pressure-induced orientational ordering of monolayers, promoting film stability. This behavior is lost as nonideality is introduced into the substrate and chain patterning on the surface becomes disordered. The presence of surface roughness is found to reduce film stability, with localization of wear observed for chain attachment sites nearest the interface of contact. The influence of substrate nonideality on monolayer degradation is shown to diminish as chain length is increased.

A coarse-grained water model is developed using multistate iterative Boltzmann inversion. Following previous work, the k -means algorithm is used to dynamically map multiple water molecules to a single coarse-grained bead, allowing the use of structure-based coarse-graining methods. The model is derived to match the bulk and interfacial properties of liquid water and improves upon previous work that used single state iterative Boltzmann inversion. The model accurately reproduces the density and structural correlations of water at 305 K and 1.0 atm, stability of a liquid droplet at 305 K, and shows little tendency to crystallize at physiological conditions. This work also illustrates several advantages of using multistate iterative Boltzmann inversion for deriving generally applicable coarse-grained forcefields.

Small bowel accounts for only 0.5% of cancer cases in the US but incidence rates have been rising at 2.4% per year over the past decade. One-third of these are adenocarcinomas but little is known about their molecular pathology and no molecular markers are available for clinical use. Using a retrospective 28 patient matched normal-tumor cohort, next-generation sequencing, gene expression arrays and CpG methylation arrays were used for molecular profiling. Next-generation sequencing identified novel mutations in IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT1, RET, NOTCH1 and ERBB4. Array data revealed 17% of CpGs and 5% of RNA transcripts assayed to be differentially methylated and expressed respectively (p < 0.01). Merging gene expression and DNA methylation data revealed CHN2 as consistently hypermethylated and downregulated in this disease (Spearman -0.71, p < 0.001). Mutations in TP53 which were found in more than half of the cohort (15/28) and Kazald1 hypomethylation were both were indicative of poor survival (p = 0.03, HR = 3.2 and p = 0.01, HR = 4.9 respectively). By integrating high-throughput mutational, gene expression and DNA methylation data, this study reveals for the first time the distinct molecular profile of small bowel adenocarcinoma and highlights potential clinically exploitable markers.

Grafting polymers to nanoparticles is one approach used to control and enhance the structure and properties of nanomaterials. However, predicting the aggregation behavior of tethered nanoparticles (TNPs) is a somewhat trial and error process as a result of the large number of possible polymer tethers, nanoparticles, and solvent species that can be studied. With the main goal of understanding how to control the dispersion and aggregation of TNP systems, molecular simulations and the hetero-statistical associating fluid theory for potentials of variable range have been used to calculate the fluid phase equilibrium of TNPs in both vacuum and in simple solvents under a wide range of conditions. The role of graft length, graft density, and solvent interactions is examined and trends established. Additionally, the fluid distribution ratio (k value) is used to study the solubility of TNPs in industrially relevant solvents including carbon dioxide, nitrogen, propane, and ethylene.

The fluid-solid phase transition behavior of nano-confined Lennard-Jones fluids as a function of temperature and degree of nanoconfinement has been studied via statistical temperature molecular dynamics (STMD). The STMD method allows the direct calculation of the density of states and thus the heat capacity with high efficiency. The fluids are simulated between parallel solid surfaces with varying pore sizes, wall-fluid interaction energies, and registry of the walls. The fluid-solid phase transition behavior has been characterized through determination of the heat capacity. The results show that for pores of ideal-spacing, the order-disorder transition temperature (T(ODT)) is reduced as the pore size increases until values consistent with that seen in a bulk system. Also, as the interaction between the wall and fluid is reduced, T(ODT) is reduced due to weak constraints from the wall. However, for non-ideal spacing pores, quite different behavior is obtained, e.g., generally T(ODT) are largely reduced, and T(ODT) is decreased as the wall constraint becomes larger. For unaligned walls (i.e., whose lattices are not in registry), the fluid-solid transition is also detected as T is reduced, indicating non-ideality in orientation of the walls does not impact the formation of a solid, but results in a slight change in T(ODT) compared to the perfectly aligned systems. The STMD method is demonstrated to be a robust way for probing the phase transitions of nanoconfined fluids systematically, enabling the future examination of the phase transition behavior of more complex fluids.

The tribology of 2-methacryloyloxyethyl phosphorylcholine monolayers in water is studied using molecular dynamics simulations. Our results show two distinct shear regimes where the first is dominated by hydration lubrication, exhibiting near zero friction coefficients, and the second by chain-chain interactions, resembling monomer-supported lubrication. These results provide insight into the hydration lubrication mechanism - a phenomena thought to underlie the extremely efficient lubrication provided by surfaces functionalized with polyzwitterionic polymer brushes and the mammalian synovial joint.

Interfacial properties of n-alkylsilane monolayers on silica have been investigated with molecular dynamics simulations using both reactive and classical (i.e., nonreactive) force fields. A synthesis mimetic simulation (SMS) procedure using the reactive force field ReaxFF has been developed to mimic the experimental processing of silicon wafers involved in the preparation of alkylsilane monolayers; in the SMS procedure, amorphous silica surfaces are generated and exposed to hydrogen peroxide (H2O2) to create a hydroxide surface layer. Alkylsilane monolayers are then assembled on these surfaces, and their behavior is studied. To investigate the impact of the SMS procedure on monolayer properties, simulations have also been performed using more idealized monolayers assembled on crystalline surfaces and non-H2O2-processed amorphous surfaces. The simulations reported here demonstrate that processing-induced silica surface roughness plays a key role in the structure and frictional performance of monolayers. Furthermore, ignoring these effects results in a significant underestimation of the coefficient of friction and an overestimation of the orientational ordering of the monolayers.

The vapor pressure of four liquid perfluoroalkylalkanes (CF3(CF2)n(CH2)mCH3; n = 3, m = 4,5,7; n = 5, m = 5) was measured as a function of temperature between 278 and 328 K. Molar enthalpies of vaporization were calculated from the experimental data, and the results were compared with data from the literature for the corresponding alkanes and perfluoroalkanes. The heterosegmented statistical associating fluid theory was used to interpret the results at the molecular level both with and without the explicit inclusion of the dipolar nature of the molecules. Additionally, ab initio calculations were performed for all perfluoroalkylalkanes studied to determine the dipole moment to be used in the theoretical calculations. We demonstrate that the inclusion of a dipolar term is essential for describing the vapor-liquid equilibria of perfluoroalkylalkanes. It is also shown that vapor-liquid equilibria in these compounds result from a subtle balance between dipolar interactions, which decrease the vapor pressure, and the relatively weak dispersive interactions between the hydrogenated and fluorinated segments.

In this work, an extension is proposed to the standard iterative Boltzmann inversion (IBI) method used to derive coarse-grained potentials. It is shown that the inclusion of target data from multiple states yields a less state-dependent potential, and is thus better suited to simulate systems over a range of thermodynamic states than the standard IBI method. The inclusion of target data from multiple states forces the algorithm to sample regions of potential phase space that match the radial distribution function at multiple state points, thus producing a derived potential that is more representative of the underlying interactions. It is shown that the algorithm is able to converge to the true potential for a system where the underlying potential is known. It is also shown that potentials derived via the proposed method better predict the behavior of n-alkane chains than those derived via the standard IBI method. Additionally, through the examination of alkane monolayers, it is shown that the relative weight given to each state in the fitting procedure can impact bulk system properties, allowing the potentials to be further tuned in order to match the properties of reference atomistic and/or experimental systems.

Ceramides are known to be a key component of the stratum corneum, the outermost protective layer of the skin that controls barrier function. In this work, molecular dynamics simulations are used to examine the behavior of ceramide bilayers, focusing on non-hydroxy sphingosine (NS) and non-hydroxy phytosphingosine (NP) ceramides. Here, we propose a modified version of the CHARMM force field for ceramide simulation, which is directly compared to the more commonly used GROMOS-based force field of Berger (Biophys. J. 1997, 72); while both force fields are shown to closely match experiment from a structural standpoint at the physiological temperature of skin, the modified CHARMM force field is better able to capture the thermotropic phase transitions observed in experiment. The role of ceramide chemistry and its impact on structural ordering is examined by comparing ceramide NS to NP, using the validated CHARMM-based force field. These simulations demonstrate that changing from ceramide NS to NP results in changes to the orientation of the OH groups in the lipid headgroups. The arrangement of OH groups perpendicular to the bilayer normal for ceramide NP, verse parallel for NS, results in the formation of a distinct hydrogen bonding network, that is ultimately responsible for shifting the gel-to-liquid phase transition to higher temperature, in direct agreement with experiment.

Two different techniques - replica-exchange Wang-Landau (REWL) and statistical temperature molecular dynamics (STMD) - were applied to systematically study the phase transition behavior of self-assembling lipids as a function of temperature using an off-lattice lipid model. Both methods allow the direct calculation of the density of states with improved efficiency compared to the original Wang-Landau method. A 3-segment model of amphiphilic lipids solvated in water has been studied with varied particle interaction energies (ε) and lipid concentrations. The phase behavior of the lipid molecules with respect to bilayer formation has been characterized through the calculation of the heat capacity as a function of temperature, in addition to various order parameters and general visual inspection. The simulations conducted by both methods can go to very low temperatures with the whole system exhibiting well-ordered structures. With optimized parameters, several bilayer phases are observed within the temperature range studied, including gel phase bilayers with frozen water, mixed water (i.e., frozen and liquid water), and liquid water, and a more fluid bilayer with liquid water. The results obtained from both methods, STMD and REWL, are consistently in excellent agreement with each other, thereby validating both the methods and the results.

In nature, processive and non-processive cellulase enzymes deconstruct cellulose to soluble sugars. From structural studies, the consensus is that processive cellulases exhibit tunnels lined with aromatic and polar residues, whereas non-processive cellulases exhibit open clefts with fewer ligand contacts. To gain additional insight into the differences between processive and non-processive cellulases, we examine the glycoside hydrolase family 7 (GH7) cellobiohydrolase, Cel7A, and the endoglucanase, Cel7B, from Trichoderma reesei with molecular simulation. We compare properties related to processivity and compute the binding affinity changes for mutation of four aromatic residues lining the Cel7A active site tunnel and Cel7B cleft to alanine. For the wild-type enzymes, dissimilar behavior is observed at nearly every glucopyranose-binding site from -7 to +2, except in the -2 site, suggesting that the structural differences directly around the catalytic center and at the active site tunnel entrances and exits may all contribute to processivity in GH7s. Interestingly, the -2 site is similar in both enzymes, likely due to the significant conformational change needed in the cellodextrin ligand near this site for catalysis. Moreover, aromatic residue mutations in the Cel7A and Cel7B active sites display only small differences in binding affinity, but the ligand flexibility and enzyme-ligand interactions are only locally affected in Cel7A, whereas the entire ligand is significantly affected when any aromatic residue is mutated in Cel7B.

Configurational-bias Monte Carlo has been incorporated into the Wang-Landau method. Although the Wang-Landau algorithm enables the calculation of the complete density of states, its applicability to continuous molecular systems has been limited to simple models. With the inclusion of more advanced sampling techniques, such as configurational-bias, the Wang-Landau method can be used to simulate complex chemical systems. The accuracy and efficiency of the method is assessed using as a test case systems of linear alkanes represented by a united-atom model. With strict convergence criteria, the density of states derived from the Wang-Landau algorithm yields the correct heat capacity when compared to conventional Boltzmann sampling simulations.

The Wang-Landau (WL) Monte Carlo method has been applied to simulate the self-assembly of a lipid bilayer on a 3D lattice. The WL method differs from conventional Monte Carlo methods in that a complete density of states is obtained directly for the system, from which properties, such as the free energy, can be derived. Furthermore, from a single WL simulation, continuous curves of the average energy and heat capacity can be determined, which provide a complete picture of the phase behavior. The lipid model studied consists of 3 or 5 coarse-grained segments on lattices of varying sizes, with the empty lattice sites representing water. A bilayer structure is found to form at low temperatures, with phase transitions to clusters as temperature increases. For 3-segment chains, varying lattice sizes were studied, with the observation that the ratio of chain number to lattice area (i.e., area per lipid) affects the phase transition temperature. At small ratios, only one phase transition occurs between the bilayer and cluster phases, while at high lipid ratios the phase transition occurs in a two-step process with a stable intermediate phase. This second phase transition was not observed in conventional Metropolis Monte Carlo simulations on the same model, demonstrating the advantage of being able to perform a complete scan of the whole temperature range with the WL method. For longer 5-segment chains similar phase transitions are also observed with changes in temperature. In the WL method, due to the extensive nature of the energy, the number of energy bins required to represent the density of states increases as the system size increases and so limits its practical application to larger systems. To improve this, an extension of the WL algorithm, the statistical-temperature Monte Carlo method that allows simulations with larger energy bin sizes, has recently been proposed and is implemented in this work for the 3-segment lattice model. The results obtained are in good agreement with the original WL method and appear to be independent of the energy bin size used.

Because of small surface area to volume ratios nanoscale devices can exhibit dominant surface forces that can quickly degrade unlubricated contacting surfaces. While fluorinated materials have been widely used as lubricants, because of their low critical surface tension and high thermal and mechanical stability, fluorinated monolayer coatings, which are suitable for lubricating nanoscale devices, are less effective as lubricants. Although fluorinated monolayers are more stable than their hydrocarbon counterparts against elevated temperature and humidity, they are known to exhibit higher frictional forces. To overcome this issue, here we study mixed monolayers composed of both hydrocarbon and fluorocarbon chains. Hydrocarbon-based monolayers have been widely studied and shown to improve frictional properties and device life. To investigate the frictional behavior of mixed fluorocarbon/hydrocarbon monolayers, molecular dynamics simulations of pure hydrogenated and fluorinated chains and mixed fluorinated/hydrogenated chains on silica surfaces have been performed. The adhesion and friction between the nanoconfined monolayers as a function of normal load, chain length, and chemical composition of the monolayer coating have been investigated, and mixed fluorocarbon/hydrocarbon monolayers found to outperform both pure fluorocarbon and pure hydrocarbon monolayers. Surface coverage was found to have a significant effect on the performance of all systems studied with higher surface coverage resulting in lower frictional forces. The simulations also show that when the hydrocarbon chains in the monolayer are longer than the fluorocarbon chains, a liquidlike layer is formed by the longer hydrocarbon chains that protrudes above the shorter fluorocarbon chains and aids in friction reduction. A frictional load dependence is also seen in these mixed monolayer systems because of repulsive interactions between the fluorocarbon base layer and the hydrocarbon liquidlike layer. A chain length difference of eight carbons between the base layer and the liquidlike layer was found to provide the lowest friction, while both a larger (because of increased entanglement) and a smaller (insufficient atoms between the contacting base layers to form a liquidlike layer) chain length difference increased friction.

We present a Fourier space density functional approach for hard particles with attractive interactions, which is based on a previously developed two-dimensional approach [S. Hlushak, W. Rżysko, and S. Sokołowski, J. Chem. Phys. 131, 094904 (2009)] for hard-sphere chains. The interactions are incorporated by means of a three-dimensional Fourier image of the direct correlation function that is obtained from the first-order mean-spherical approximation. In order to improve the computational efficiency, we make extensive use of fast Fourier transforms for calculating density convolution integrals. A two-dimensional implementation of the new density functional approach, based on the expansion of the functional around the bulk fluid density, is used to study structure and adsorption of two model fluids in narrow cylindrical pores. We also investigate two methods that improve the accuracy of the theory as compared to the conventional DFT approach, which expands the free energy functional around the bulk fluid density: One a variant of the reference fluid density functional theory used by Gillespie et al. [Phys. Rev. E 68, 031503 (2003)], and the second a weighted density approach with energy route thermodynamics. Results from these two methods are compared to the conventional approach and also to the results of Monte Carlo simulations. We find that the method of Gillespie et al. and the weighted density approach with energy route thermodynamics yield significant improvement over the conventional approach.

Coarse-grained (CG) models have proven to be very effective tools in the study of phenomena or systems that involve large time- and length-scales. By decreasing the degrees of freedom in the system and using softer interactions than seen in atomistic models, larger timesteps can be used and much longer simulation times can be studied. CG simulations are widely used to study systems of biological importance that are beyond the reach of atomistic simulation, necessitating a computationally efficient and accurate CG model for water. In this review, we discuss the methods used for developing CG water models and the relative advantages and disadvantages of the resulting models. In general, CG water models differ with regards to how many waters each CG group or bead represents, whether analytical or tabular potentials have been used to describe the interactions, and how the model incorporates electrostatic interactions. Finally, how the models are parameterized depends on their application, so, while some are fitted to experimental properties such as surface tension and density, others are fitted to radial distribution functions extracted from atomistic simulations.

Monolayers presenting methyl-terminated (hydrophobic) and hydroxyl-terminated (hydrophilic) surfaces on silica have been studied by molecular dynamics simulation and the effects of hydrogen bonding, chain length, and chain mixing on the frictional properties determined. The hydroxyl-terminated monolayers were found to show large adhesion zones as a result of strong interfacial interlayer hydrogen bonds; the interfacial sliding forces observed in the hydroxyl-terminated monolayers being one order of magnitude higher than the interfacial forces for the hydrophobic surfaces at the characteristic point of zero-load. Mixed hydroxyl- and methyl-terminated monolayers of equal length were found to exhibit intermediate shear stress values between those observed for pure monolayers, with the magnitude of the shear stress depending on the surface content of the hydroxyl-terminated chains. For mixed monolayers of unequal chain lengths, at high loads a maximum in the magnitude of the shear stress as a function of the length of the methyl-terminated chain was observed due to the creation of a buffer zone between the hydroxyl-terminated chains that produces strong hydrogen-bonding interactions. The effect of a constant normal load or constant separation simulation ensemble on the results has also been studied and in general found to have minimal influence on the observed behavior, although some differences are observed for the shear stress at intermediate normal loads due to the formation of stronger hydrogen bond networks at constant load compared to constant separation.

Carbohydrate-binding modules (CBMs) are ubiquitous components of glycoside hydrolases, which degrade polysaccharides in nature. CBMs target specific polysaccharides, and CBM binding affinity to cellulose is known to be proportional to cellulase activity, such that increasing binding affinity is an important component of performance improvement. To ascertain the impact of protein and glycan engineering on CBM binding, we use molecular simulation to quantify cellulose binding of a natively glycosylated Family 1 CBM. To validate our approach, we first examine aromatic-carbohydrate interactions on binding, and our predictions are consistent with previous experiments, showing that a tyrosine to tryptophan mutation yields a 2-fold improvement in binding affinity. We then demonstrate that enhanced binding of 3-6-fold over a nonglycosylated CBM is achieved by the addition of a single, native mannose or a mannose dimer, respectively, which has not been considered previously. Furthermore, we show that the addition of a single, artificial glycan on the anterior of the CBM, with the native, posterior glycans also present, can have a dramatic impact on binding affinity in our model, increasing it up to 140-fold relative to the nonglycosylated CBM. These results suggest new directions in protein engineering, in that modifying glycosylation patterns via heterologous expression, manipulation of culture conditions, or introduction of artificial glycosylation sites, can alter CBM binding affinity to carbohydrates and may thus be a general strategy to enhance cellulase performance. Our results also suggest that CBM binding studies should consider the effects of glycosylation on binding and function.

As part of a combined experimental and theoretical study of the thermodynamic properties of perfluoroalkylalkanes (PFAAs), the liquid density of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), and perfluorobutyloctane (F4H8) was measured as a function of temperature from 278.15 to 353.15 K and from atmospheric pressure to 70 MPa. The liquid densities of n-perfluoropentane, n-perfluorohexane, n-perfluorooctane, and n-perfluorononane were also measured at room pressure over the same temperature range. The PVT behavior of the PFAAs was also studied using the SAFT-VR equation of state. The PFAA molecules were modeled as heterosegmented diblock chains, using different parameters for the alkyl and perfluoroalkyl segments, that were developed in earlier work. Through this simple approach, we are able to predict the thermodynamic behavior of the perfluoroalkylalkanes, without fitting to any experimental data for the systems being studied. Molecular dynamics simulations have also been performed and used to calculate the densities of the perfluoroalkylalkanes studied.

Proteins employ aromatic residues for carbohydrate binding in a wide range of biological functions. Glycoside hydrolases, which are ubiquitous in nature, typically exhibit tunnels, clefts, or pockets lined with aromatic residues for processing carbohydrates. Mutation of these aromatic residues often results in significant activity differences on insoluble and soluble substrates. However, the thermodynamic basis and molecular level role of these aromatic residues remain unknown. Here, we calculate the relative ligand binding free energy by mutating tryptophans in the Trichoderma reesei family 6 cellulase (Cel6A) to alanine. Removal of aromatic residues near the catalytic site has little impact on the ligand binding free energy, suggesting that aromatic residues immediately upstream of the active site are not directly involved in binding, but play a role in the glucopyranose ring distortion necessary for catalysis. Removal of aromatic residues at the entrance and exit of the Cel6A tunnel, however, dramatically impacts the binding affinity, suggesting that these residues play a role in chain acquisition and product stabilization, respectively. The roles suggested from differences in binding affinity are confirmed by molecular dynamics and normal mode analysis. Surprisingly, our results illustrate that aromatic-carbohydrate interactions vary dramatically depending on the position in the enzyme tunnel. As aromatic-carbohydrate interactions are present in all carbohydrate-active enzymes, these results have implications for understanding protein structure-function relationships in carbohydrate metabolism and recognition, carbon turnover in nature, and protein engineering strategies for biomass utilization. Generally, these results suggest that nature employs aromatic-carbohydrate interactions with a wide range of binding affinities for diverse functions.

As part of a systematic study of the thermophysical properties of two important classes of fluorinated organic compounds (perfluoroalkanes and perfluoroalkylalkanes), viscosity measurements of four n-perfluoroalkanes and five perfluoroalkylalkanes have been carried out at atmospheric pressure and over a wide range of temperatures (278-353 K). From the experimental results the contribution to the viscosity from the CF(2) and CF(3) groups as a function of temperature have been estimated. Similarly, the contributions for CH(2) and CH(3) groups in n-alkanes have been determined using literature data. For perfluoroalkylalkanes, the viscosity results were interpreted in terms of the contributions of the constituent CF(2), CF(3), CH(2), and CH(3) groups, the deviations from ideality on mixing hydrogenated and fluorinated chains, and the contribution due to the formation of the CF(2)-CH(2) bond. A standard empirical group contribution method (Sastri-Rao method) has also been used to estimate the viscosities of the perfluoroalkylalkanes. Finally, to obtain molecular level insight into the behavior of these molecules, all-atom molecular dynamics simulations have been performed and used to calculate the densities and viscosities of the perfluoroalkylalkanes studied. Although both quantities are underestimated compared to the experimental data, with the viscosities showing the largest deviations, the trends observed in the experimental viscosities are captured., (© 2011 American Chemical Society)

We report the frictional performance and long-term tribological stability of various alkyl silane monolayer films on silicon by using pin-on-disk tribometry at ambient conditions. We show that the durability of monolayers derived from n-alkyltrichlorosilanes on silicon increases exponentially with the chain length of the silane precursor, which we relate to the cohesive energy of these monolayers through molecular dynamics simulations. X-ray photoelectron spectroscopy (XPS) was used to show that tribological damage consisted of the loss of molecular components that could be partially replaced upon exposure to a solution containing perfluorinated silane precursors. For monolayers derived from n-octadecyltrichlorosilane, a critical load was identified to be approximately 250 mN (200 MPa), above which failure of films occurred within 100 cycles of testing. Monolayers with hydroxyl surfaces exhibited reduced stabilities due to stronger tip-surface interactions. Monolayers with the capability for cross-linking exhibited much greater stabilities than monolayers where cross-linking was limited or prevented. Collectively, these results demonstrate that the mechanical durability of monolayers when subjected to a tribological load is greatly enhanced by maximizing dispersional interactions and cross-linking and minimizing tip-surface interactions.

The solubility of xenon in liquid n-pentane and n-hexane has been studied experimentally, theoretically, and by computer simulation. Measurements of the solubility are reported for xenon + n-pentane as a function of temperature from 254 to 305 K. The uncertainty in the experimental data is less than 0.15%. The thermodynamic functions of solvation such as the standard Gibbs energy, enthalpy, and entropy of solvation have been calculated from Henry's law coefficients for xenon + n-pentane solutions and also for xenon + n-hexane, which were reported in previous work. The results provide a further example of the similarity between the xenon + n-alkane interaction and the n-alkane + n-alkane interactions. Using the SAFT-VR approach we were able to quantitatively predict the experimental solubility for xenon in n-pentane and semiquantitatively that of xenon in n-hexane using simple Lorentz-Berthelot combining rules to describe the unlikely interaction. Henry's constants at infinite dilution for xenon + n-pentane and xenon + n-hexane were also calculated by Monte Carlo simulation using a united atom force field to describe the n-alkane and the Widom test particle insertion method.

Fungi and bacteria secrete glycoprotein cocktails to deconstruct cellulose. Cellulose-degrading enzymes (cellulases) are often modular, with catalytic domains for cellulose hydrolysis and carbohydrate-binding modules connected by linkers rich in serine and threonine with O-glycosylation. Few studies have probed the role that the linker and O-glycans play in catalysis. Since different expression and growth conditions produce different glycosylation patterns that affect enzyme activity, the structure-function relationships that glycosylation imparts to linkers are relevant for understanding cellulase mechanisms. Here, the linker of the Trichoderma reesei Family 7 cellobiohydrolase (Cel7A) is examined by simulation. Our results suggest that the Cel7A linker is an intrinsically disordered protein with and without glycosylation. Contrary to the predominant view, the O-glycosylation does not change the stiffness of the linker, as measured by the relative fluctuations in the end-to-end distance; rather, it provides a 16 Å extension, thus expanding the operating range of Cel7A. We explain observations from previous biochemical experiments in the light of results obtained here, and compare the Cel7A linker with linkers from other cellulases with sequence-based tools to predict disorder. This preliminary screen indicates that linkers from Family 7 enzymes from other genera and other cellulases within T. reesei may not be as disordered, warranting further study., (Copyright © 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

The cellular membrane functions as a regulating barrier between the intracellular and extracellular regions. For a molecule to reach the interior of the cell from the extracellular fluid, it must diffuse across the membrane, via either active or passive transport. The rigid structure of lipid bilayers, which are a key component of cellular membranes, prohibit simple diffusion of most particles, while vital nutrients are transported to the interior by specific mechanisms, such as ion channels and transport proteins. Although the cellular membrane provides the cell with protection against unwanted toxins that may be in the extracellular medium, some foreign particles can reach the interior of the cell, resulting in irregularities in cellular function. This behavior is particularly noted for permeants with compact molecular structure, suggesting that common nanoscale building blocks, such as fullerenes, may enter into the interior of a cell. To gauge the propensity for such particles to cross the membrane, we have computed the Gibbs free energy of transfer along the axis normal to the bilayer surface for two nanoscale building blocks, C(60) and a hydrogen-terminated polyhedral oligomeric silsequioxane (H-POSS) monomer, in a hydrated dipalmitoylphosphatidylcholine (DPPC) bilayer using molecular dynamics simulations and potential of mean force calculations. The studies show that C(60) has a substantial energetic preference for the soft polymer region of the lipid bilayer system, below the water/bilayer interface, with a transition energy from bulk water of -19.8 kcal/mol. The transition of C(60) from the bulk water to the center of the bilayer, while also energetically favorable, has to overcome a +5.9 kcal/mol energetic barrier in the hydrophobic lipid tail region. The H-POSS simulations indicate an energy minimum at the water-bilayer interface, with an energy of -10.9 kcal/mol; however, a local minimum of -2.7 kcal/mol is also observed in the hydrophobic dense aliphatic region. The energy barrier seen in the hydrophobic core region of the C(60) study is likely due to the significant penalty associated with inserting the relatively large particle into such a dense region. In contrast, whereas H-POSS is found to be subject to an energetic penalty upon insertion into the bilayer, the relatively small size of the H-POSS solute renders this penalty less significant. The energy barrier seen in the soft polymer region for the H-POSS monomer is primarily attributed to the lack of favorable solute-bilayer electrostatic interactions, which are present in the interfacial region, and fewer van der Waals interactions in the soft polymer region than the dense aliphatic region. These results indicate that C(60) may partition into the organic phase of the DPPC/water system, given the favorable free energies in the soft polymer and dense aliphatic regions of the bilayer, and H-POSS is likely to partition near the water-bilayer interface, where the particle has low-energy electrostatic interactions with the polar head groups of the bilayer.

Developing accurate models of water for use in computer simulations is important for the study of many chemical and biological systems, including lipid bilayer self-assembly. The large temporal and spatial scales needed to study such self-assembly have led to the development and application of coarse-grained models for the lipid-lipid, lipid-solvent, and solvent-solvent interactions. Unfortunately, popular center-of-mass-based coarse-graining techniques are limited to modeling water with one water per be ad. In this work, we have utilized the K-means algorithm to determine the optimal clustering of waters to allow the mapping of multiple waters to single coarse-grained beads. Through the study of a simple mixture between water and an amphiphilic solute (1-pentanol), we find a four-water bead model has the optimal balance between computational efficiency and accurate solvation and structural properties when compared to water models ranging from one to nine waters per bead. The four-water model was subsequently utilized in studies of the solvation of hexadecanoic acid and the structure, as measured via radial distribution functions, for the hydrophobic tails and the bulk water phase were found to agree well with experimental data and their atomistic target.