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The intrinsic sampling method (ISM) is a powerful tool that allows the exploration of interfacial properties from molecular simulations by fitting a function that represents the local boundary between two phases. However, owing to the non-physical nature of an "intrinsic" surface, there remains an ambiguity surrounding the comparison of theoretical properties with the physical world. It is therefore important that the ISM remains internally consistent when reproducing simulated properties which match experiments, such as the surface tension or interfacial density distribution. We show that the current ISM procedure causes an over-fitting of the surface to molecules in the interface region, leading to a biased distribution of curvature at these molecular coordinates. We assert that this biased distribution is a cause of the disparity between predicted interfacial densities upon convolution to a laboratory frame, an artefact which has been known to exist since the development of the ISM. We present an improvement to the fitting procedure of the ISM in an attempt to alleviate the ambiguity surrounding the true nature of an intrinsic surface. Our "surface reconstruction" method is able to amend the shape of the interface so as to reproduce the global curvature distribution at all sampled molecular coordinates. We present the effects that this method has on the ISM predicted structure of a simulated Lennard-Jones fluid air-liquid interface. Additionally, we report an unexpected relationship between surface thermodynamic predictions of our reconstructed ISM surfaces and those of extended capillary wave theory, which is of current interest. [ABSTRACT FROM AUTHOR]

We present an unexpected finite size effect affecting interfacial molecular simulations that is proportional to the width-to-surface-area ratio of the bulk phase Ll/A. This finite size effect has a significant impact on the variance of surface tension values calculated using the virial summation method. A theoretical derivation of the origin of the effect is proposed, giving a new insight into the importance of optimising system dimensions in interfacial simulations. We demonstrate the consequences of this finite size effect via a new way to estimate the surface energetic and entropic properties of simulated air-liquid interfaces. Our method is based on macroscopic thermodynamic theory and involves comparing the internal energies of systems with varying dimensions. We present the testing of these methods using simulations of the TIP4P/2005 water forcefield and a Lennard-Jones fluid model of argon. Finally, we provide suggestions of additional situations, in which this finite size effect is expected to be significant, as well as possible ways to avoid its impact. [ABSTRACT FROM AUTHOR]

The behavior of lubricants at operational conditions, such as at high pressures, is a topic of great industrial interest. In particular, viscosity and the viscosity-pressure relation are especially important for applications and their determination by computational simulations is very desirable. In this study, we evaluate methods to compute these quantities based on fully atomistic molecular dynamics simulations, which are computationally demanding but also have the potential to be most accurate. We used the 9,10-dimethyloctadecane molecule, main component of PAO-2 base oil as the lubricant for our tests. The methods used for the viscosity simulations are the Green-Kubo equilibrium molecular dynamics (EMD-GK) and nonequilibrium molecular dynamics (NEMD), at pressures of up to 1.0 GPa and various temperatures (40-150 degrees Celsius). We present the theory behind these methods and investigate how the simulation parameters affect the results obtained, to ensure viscosity convergence with respect to the simulation intervals and all other parameters. We show that, by using each method in its regime of applicability, we can achieve good agreement between simulated and measured values. NEMD simulations at high pressures captured zero shear viscosity successfully; while at 40 degrees Celsius, EMD-GK is only applicable to pressures up to 0.3 GPa, where the viscosity is lower. In NEMD, longer and multiply repeated simulations improve the confidence interval of viscosity, which is essential at lower pressures. Another aspect of these methods is the choice of the utilized force field for the atomic interactions. This was investigated by selecting two different commonly used force fields. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in TB granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells. [ABSTRACT FROM AUTHOR]

Hypothesis Silanol groups at the silica–water interface determine not only the surface charge, but also have an important role in the binding of ions and biomolecules. As the pH is increased above pH 2, the silica surface develops a net negative charge primarily due to deprotonation of the silanol group. An improved understanding of the energetics and mechanisms of this fundamentally important process would further understanding of the relevant dynamics. Simulations Density Functional Theory ab initio molecular dynamics and geometry optimisations were used to investigate the mechanisms of surface neutralisation and charging in the presence of OH - and H 3 O + respectively. This charging mechanism has received little attention in the literature. Findings The protonation or deprotonation of isolated silanols in the presence of H 3 O + or OH - , respectively, was shown to be a highly rapid, exothermic reaction with no significant activation energy. This process occurred via a concerted motion of the protons through ‘water wires’. Geometry optimisations of large water clusters at the silica surface demonstrated proton transfer to the surface occurring via the rarely discussed ‘proton holes’ mechanism. This indicates that surface protonation is possible even when the hydronium ion is distant (at least 4 water molecules separation) from the surface. [ABSTRACT FROM AUTHOR]

Theuse of the Zwanzig equation in the calculation of single-stepperturbations to provide first-principles (ab initio) quantum mechanics (QM) correction terms to molecular mechanics(MM) free energy cycles is well established. A rigorous test of theability to converge such calculations would be very useful in thiscontext. In this work, we perform a direct assessment of the convergenceof the MM to QM perturbation, by attempting the reverse QM to MM perturbation.This required the generation of extensive QM molecular dynamics trajectories,using density functional theory (DFT), within the representative biologicalsystem of a DNA adenosine–thymidine dimer. Over 100 ps of dynamicswith the PBE functional and 6.25 ps with the LDA functional were generated.We demonstrate that calculations with total potential energies arevery poorly convergent due to a lack of overlap of phase space distributionsbetween ensembles. While not theoretically rigorous, the use of interactionenergies provides far superior convergence, despite the presence ofnonclassical charge transfer effects within the DFT trajectories.The source of poor phase space overlap for total energies is diagnosed,the approximate quantification of overlaps suggesting that even forthe comparatively simple system considered here convergence of totalenergy calculations within a reasonable simulation time is unfeasible. [ABSTRACT FROM AUTHOR]

In the repair of double-strand breaks of DNA by homologous recombination the recombinase protein RAD51 has its functions controlled by the breast cancer susceptibility protein BRCA2. BRCA2 can bind to RAD51 via the BRC repeats BRC1-BRC8, which are eight conserved sequence motifs in BRCA2 of about 35 amino acids. We have carried out a series of extensive unrestrained atomistic molecular dynamics (MD) simulations in explicit water for a total time period of 248 ns, in order to study the dynamical behaviour and conformations of the complexes between the hairpin loop region of the BRC repeats and RAD51. Our simulations have allowed us to investigate the conformations adopted by the BRC repeats both while bound to RAD51 and while isolated. These conformations are rationalised through an analysis of the inter- and intra-molecular backbone and side chain bonding interactions in all the eight human BRC repeats as well as in a single-point mutation of BRC4. The differences in sequence result in differences in the interactions between the BRC repeats and the RAD51 protein but these do not appear to disrupt the binding in any of the BRC-RAD51 complexes as there are always a number of key residues remaining which allow a sufficient number of interactions to stabilise the complexes. [ABSTRACT FROM AUTHOR]

The estimation of metal nanoparticle diameter by analysis of extended x-ray absorption fine structure (EXAFS) data from coordination numbers is nontrivial, particularly for particles <5 nm in diameter, for which the undercoordination of surface atoms becomes an increasingly significant contribution to the average coordination number. These undercoordinated atoms have increased degrees of freedom over those within the core of the particle, which results in an increase in the degree of structural disorder with decreasing particle size. This increase in disorder, however, is not accounted for by the standard means of EXAFS analysis, where each coordination shell is fitted with a single bond length and disorder term. In addition, the surface atoms of nanoparticles have been observed to undergo a greater contraction than those in the core, further increasing the range of bond distances. Failure to account for this structural change results in an increased disorder being measured, and therefore, a lower apparent coordination number and corresponding particle size are found. Here, we employ molecular dynamics (MD) simulations for a range of nanoparticle sizes to determine each of the nearest neighbor bond lengths, which were then binned into a histogram to construct a radial distribution function (RDF). Each bin from the histogram was considered to be a single scattering path and subsequently used in fitting the EXAFS data obtained for a series of carbon-supported platinum nanoparticles. These MD-based fits are compared with those obtained using a standard fitting model using Artemis and the standard model with the inclusion of higher cumulants, which has previously been used to account for the non-Gaussian distribution of neighboring atoms around the absorber. The results from all three fitting methods were converted to particle sizes and compared with those obtained from transmission electron microscopy (TEM) and x-ray diffraction (XRD) measurements. We find that the use of molecular dynamics simulations resulted in an improved fit over both the standard and cumulant models, in terms of both quality of fit and correlation with the known average particle size. [ABSTRACT FROM AUTHOR]

Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC) architectures, such as multicore CPUs and modern graphics processing units (GPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware platforms. We have now approached an era where multipole-based polarizable force fields can be routinely used to obtain computational results comparable to state-of-the-art density functional theory while reaching sampling statistics that are acceptable when compared to that obtained from simpler fixed partial charge force fields. [ABSTRACT FROM AUTHOR]

Schemes of increasing sophisticationfor obtaining free energiesof binding have been developed over the years, where configurationalsampling is used to include the all-important entropic contributionsto the free energies. However, the quality of the results will alsodepend on the accuracy with which the intermolecular interactionsare computed at each molecular configuration. In this context, theenergy change associated with the rearrangement of electrons (electronicpolarization and charge transfer) upon binding is a very importanteffect. Classical molecular mechanics force fields do not take thiseffect into account explicitly, and polarizable force fields and semiempiricalquantum or hybrid quantum–classical (QM/MM) calculations areincreasingly employed (at higher computational cost) to compute intermolecularinteractions in free-energy schemes. In this work, we investigatethe use of large-scale quantum mechanical calculations from first-principlesas a way of fully taking into account electronic effects in free-energycalculations. We employ a one-step free-energy perturbation (FEP)scheme from a molecular mechanical (MM) potential to a quantum mechanical(QM) potential as a correction to thermodynamic integration calculationswithin the MM potential. We use this approach to calculate relativefree energies of hydration of small aromatic molecules. Our quantumcalculations are performed on multiple configurations from classicalmolecular dynamics simulations. The quantum energy of each configurationis obtained from density functional theory calculations with a near-completepsinc basis set on over 600 atoms using the ONETEP program. [ABSTRACT FROM AUTHOR]

We present a computational approach for the simulation of extended x-ray absorption fine structure (EXAFS) spectra of nanoparticles directly from molecular dynamics simulations without fitting any of the structural parameters of the nanoparticle to experimental data. The calculation consists of two stages. First, a molecular dynamics simulation of the nanoparticle is performed and then the EXAFS spectrum is computed from "snapshots" of structures extracted from the simulation. A probability distribution function approach calculated directly from the molecular dynamics simulations is used to ensure a balanced sampling of photoabsorbing atoms and their surrounding scattering atoms while keeping the number of EXAFS calculations that need to be performed to a manageable level. The average spectrum from all configurations and photoabsorbing atoms is computed as an Au L3-edge EXAFS spectrum with the FEFF 8.4 package, which includes the self-consistent calculation of atomic potentials. We validate and apply this approach in simulations of EXAFS spectra of gold nanoparticles with sizes between 20 and 60 Å. We investigate the effect of size, structural anisotropy, and thermal motion on the gold nanoparticle EXAFS spectra and we find that our simulations closely reproduce the experimentally determined spectra. [ABSTRACT FROM AUTHOR]