A classical view on nonclassical nucleation.

Understanding and controlling nucleation is important for many crystallization applications. Calcium carbonate (CaCO3) is often used as a model system to investigate nucleation mechanisms. Despite its great importance in geology, biology, and many industrial applications, CaCO3 nucleation is still a topic of intense discussion, with new pathways for its growth from ions in solution proposed in recent years. These new pathways include the so-called nonclassical nucleation mechanism via the assembly of thermodynamically stable prenucleation clusters, as well as the formation of a dense liquid precursor phase via liquid-liquid phase separation. Here, we present results from a combined experimental and computational investigation on the precipitation of CaCO3 in dilute aqueous solutions. We propose that a dense liquid phase (containing 4-7 H2O per CaCO3 unit) forms in supersaturated solutions through the association of ions and ion pairs without significant participation of larger ion clusters. This liquid acts as the precursor for the formation of solid CaCO3 in the form of vaterite, which grows via a net transfer of ions from solution according to z Ca2+ + z CO32- → z CaCO3 The results show that all steps in this process can be explained according to classical concepts of crystal nucleation and growth, and that long-standing physical concepts of nucleation can describe multistep, multiphase growth mechanisms.

Sodium Binding Sites and Permeation Mechanism in the NaChBac Channel: A Molecular Dynamics Study.

NaChBac was the first discovered bacterial sodium voltage-dependent channel, yet computational studies are still limited due to the lack of a crystal structure. In this work, a pore-only construct built using the NavMs template was investigated using unbiased molecular dynamics and metadynamics. The potential of mean force (PMF) from the unbiased run features four minima, three of which correspond to sites IN, CEN, and HFS discovered in NavAb. During the run, the selectivity filter (SF) is spontaneously occupied by two ions, and frequent access of a third one is often observed. In the innermost sites IN and CEN, Na+ is fully hydrated by six water molecules and occupies an on-axis position. In site HFS sodium interacts with a glutamate and a serine from the same subunit and is forced to adopt an off-axis placement. Metadynamics simulations biasing one and two ions show an energy barrier in the SF that prevents single-ion permeation. An analysis of the permeation mechanism was performed both computing minimum energy paths in the axial-axial PMF and through a combination of Markov state modeling and transition path theory. Both approaches reveal a knock-on mechanism involving at least two but possibly three ions. The currents predicted from the unbiased simulation using linear response theory are in excellent agreement with single-channel patch-clamp recordings.

Improved estimation of density of states for Monte Carlo sampling via MBAR.

We present a new method to calculate the density of states using the multistate Bennett acceptance ratio (MBAR) estimator. We use a combination of parallel tempering (PT) and multicanonical simulation to demonstrate the efficiency of our method in a statistical model of sampling from a two-dimensional normal mixture and also in a physical model of aggregation of lattice polymers. While MBAR has been commonly used for final estimation of thermodynamic properties, our numerical results show that the efficiency of estimation with our new approach, which uses MBAR as an intermediate step, often improves upon conventional use of MBAR. We also demonstrate that it can be beneficial in our method to use full PT samples for MBAR calculations in cases where simulation data exhibit long correlation.

How does an amorphous surface influence molecular binding?--ovocleidin-17 and amorphous calcium carbonate.

Atomistic molecular dynamics simulations of dehydrated amorphous calcium carbonate interacting with the protein ovocleidin-17 are presented. These simulations demonstrate that the amorphisation of the calcium carbonate surface removes water structure from the surface. This reduction of structure allows the protein to bind with many residues, unlike on crystalline surfaces where binding is strongest when only a few residues are attached to the surface. Basic residues are observed to dominate the binding interactions. The implications for protein control over crystallisation are discussed.

Facet selectivity in gold binding peptides: exploiting interfacial water structure.

Peptide sequences that can discriminate between gold facets under aqueous conditions offer a promising route to control the growth and organisation of biomimetically-synthesised gold nanoparticles. Knowledge of the interplay between sequence, conformations and interfacial properties is essential for predictable manipulation of these biointerfaces, but the structural connections between a given peptide sequence and its binding affinity remain unclear, impeding practical advances in the field. These structural insights, at atomic-scale resolution, are not easily accessed with experimental approaches, but can be delivered via molecular simulation. A current unmet challenge lies in forging links between predicted adsorption free energies derived from enhanced sampling simulations with the conformational ensemble of the peptide and the water structure at the surface. To meet this challenge, here we use an in situ combination of Replica Exchange with Solute Tempering with Metadynamics simulations to predict the adsorption free energy of a gold-binding peptide sequence, AuBP1, at the aqueous Au(111), Au(100)(1 × 1) and Au(100)(5 × 1) interfaces. We find adsorption to the Au(111) surface is stronger than to Au(100), irrespective of the reconstruction status of the latter. Our predicted free energies agree with experiment, and correlate with trends in interfacial water structuring. For gold, surface hydration is predicted as a chief determining factor in peptide-surface recognition. Our findings can be used to suggest how shaped seed-nanocrystals of Au, in partnership with AuBP1, could be used to control AuNP nanoparticle morphology.

Structure and properties of citrate overlayers adsorbed at the aqueous Au(111) interface.

One of the most common means of gold nanoparticle (AuNP) biofunctionalization involves the manipulation of precursor citrate-capped AuNPs via ligand displacement. However, the molecular-level structural characteristics of the citrate overlayer adsorbed at the aqueous Au interface at neutral pH remain largely unknown. Access to atomistic-scale details of these interfaces will contribute much needed insight into how AuNPs can be manipulated and exploited in aqueous solution. Here, the structures of such citrate overlayers adsorbed at the aqueous Au(111) interface at pH 7 are predicted and characterized using atomistic molecular dynamics simulations, for a range of citrate surface densities. We find that the overlayers are disordered in the surface density range considered, and that many of their key characteristics are invariant with surface density. In particular, we predict the overlayers to have 3-D, rather than 2-D, morphologies, with the anions closest to the gold surface being oriented with their carboxylate groups pointing away from the surface. We predict both striped and island morphologies for our overlayers, depending on the citrate surface density, and in all cases we find bare patches of the gold surface are present. Our simulations suggest that both citrate-gold adsorption and citrate-counterion pairing contribute to the stability of these citrate overlayer morphologies. We also calculate the free energy of adsorption at the aqueous Au(111) interface of a single citrate molecule, and compare this with the corresponding value for a single arginine molecule. These findings enable us to predict the conditions under which ligand displacement of surface-adsorbed citrate by arginine may take place. Our findings represent the first steps toward elucidating a more elaborate, detailed atomistic-scale model relating to the biofunctionalization of citrate-capped AuNPs.

Equilibrium conformational ensemble of the intrinsically disordered peptide n16N: linking subdomain structures and function in nacre.

n16 is a framework protein family associated with biogenic mineral stabilization, thought to operate at three key interfaces in nacre: protein/ß-chitin, protein/protein, and protein/CaCO3. The N-terminal half of this protein, n16N, is known to be active in conferring this mineral stabilization and organization. While some details relating to the stabilization and organization of the mineral are known, the molecular mechanisms that underpin these processes are not yet established. To provide these molecular-scale details, here we explore current hypotheses regarding the possible subdomain organization of n16N, as related to these three interfaces in nacre, by combining outcomes of Replica Exchange with Solute Tempering molecular dynamics simulations with NMR experiments, to investigate the conformational ensemble of n16N in solution. We verify that n16N lacks a well-defined secondary structure, both with and without the presence of Ca(2+) ions, as identified from previous experiments. Our data support the presence of three different, functional subdomains within n16N. Our results reveal that tyrosine, chiefly located in the center of the peptide, plays a multifunctional role in stabilizing conformations of n16N, for intrapeptide and possibly interpeptide interactions. Complementary NMR spectroscopy data confirm the participation of tyrosine in this stabilization. The C-terminal half of n16N, lacking in tyrosine and highly charged, shows substantive conformational diversity and is proposed as a likely site for nucleation of calcium carbonate. Finally, dominant structures from our predicted conformational ensemble suggest the presentation of key residues thought to be critical to the selective binding to ß-chitin surfaces.

New insight into the stability of CaCO3 surfaces and nanoparticles via molecular simulation.

Using updated and improved atomistic models for the polymorphs of calcium carbonate and their constituent ions in solution, we revisit the question of surface energetics and nanoparticle stability. Using a simple lattice-based Monte Carlo scheme, we generate nanoparticle configurations in vacuum for all three biologically relevant polymorphs of calcium carbonate and establish that the bulk energetic ordering of polymorphs persists to the nanoscale. In aqueous environments, results based on surface enthalpy alone indicate that formation of mineral-water interfaces is marginally favorable in many cases. Including an estimate of lost entropy due to formation of structured water layers is sufficient to reverse this observation, implying a delicate balance of enthalpy and entropy at crystalline CaCO3. In contradiction to some previous studies, we find that small calcite nanoparticles with diameters in the range of 1.8-4.1 nm do not retain an ordered structure on nanosecond time scales. The consequences of these results for simulation studies of biomineralization are discussed.

Solubility of aqueous methane under metastable conditions: implications for gas hydrate nucleation.

To understand the prenucleation stage of methane hydrate formation, we measured methane solubility under metastable conditions using molecular dynamics simulations. Three factors that influence solubility are considered: temperature, pressure, and the strength of the modeled van der Waals attraction between methane and water. Moreover, the naturally formed water cages and methane clusters in the methane solutions are analyzed. We find that both lowering the temperature and increasing the pressure increase methane solubility, but lowering the temperature is more effective than increasing the pressure in promoting hydrate nucleation because the former induces more water cages to form while the latter makes them less prevalent. With an increase in methane solubility, the chance of forming large methane clusters increases, with the distribution of cluster sizes being exponential. The critical solubility, beyond which the metastable solutions spontaneously form hydrate, is estimated to be ~0.05 mole fraction in this work, corresponding to the concentration of 1.7 methane molecules/nm(3). This value agrees well with the cage adsorption hypothesis of hydrate nucleation.

GolP-CHARMM: First-Principles Based Force Fields for the Interaction of Proteins with Au(111) and Au(100).

Computational simulation of peptide adsorption at the aqueous gold interface is key to advancing the development of many applications based on gold nanoparticles, ranging from nanomedical devices to smart biomimetic materials. Here, we present a force field, GolP-CHARMM, designed to capture peptide adsorption at both the aqueous Au(111) and Au(100) interfaces. The force field, compatible with the bio-organic force field CHARMM, is parametrized using a combination of experimental and first-principles data. Like its predecessor, GolP (Iori, F.; et al. J. Comput. Chem.2009, 30, 1465), this force field contains terms to describe the dynamic polarization of gold atoms, chemisorbing species, and the interaction between sp(2) hybridized carbon atoms and gold. A systematic study of small molecule adsorption at both surfaces using the vdW-DF functional (Dion, M.; et al. Phys. Rev. Lett.2004, 92, 246401-1. Thonhauser, T.; et al. Phys. Rev. B2007, 76, 125112) is carried out to fit and test force field parameters and also, for the first time, gives unique insights into facet selectivity of gold binding in vacuo. Energetic and spatial trends observed in our DFT calculations are reproduced by the force field under the same conditions. Finally, we use the new force field to calculate adsorption energies, under aqueous conditions, for a representative set of amino acids. These data are found to agree with experimental findings.

Protein binding on stepped calcite surfaces: simulations of ovocleidin-17 on calcite {31.16} and {31.8}.

Simulations using classical molecular dynamics are reported on the binding of the protein Ovocleidin-17 to calcite stepped surfaces. vicinal surfaces ({31.8} and {31.16}) are used to obtain acute and obtuse steps. The simulations demonstrate that binding is greater at the obtuse step. A range of analytical methods is used to show the importance of surface and local water structure for protein binding. We discuss the general features of molecular binding in the light of these results. Our analysis shows that it is unlikely that Ovocleidin-17 is important in controlling crystal morphology; its main role is likely to be in controlling calcite nucleation.

Applying the Z method to estimate temperatures of melting in structure II clathrate hydrates.

Equilibrium melting temperatures for structure II THF hydrate and argon/xenon (Ar/Xe) binary hydrate have been calculated using molecular dynamics using two melting techniques, namely the Z method [Belonoshko et al., Phys. Rev. B, 2006, 73, 012201] (applied for the first time to complex molecular solids) and direct phase coexistence simulations. The two methods give results in moderate agreement: calculations with the Z method give T(fus) to be 250.7 K (0.77 katm) for THF and 244.3 K (1.86 katm) for Ar/Xe hydrate respectively; the corresponding direct phase coexistence calculations give T(fus) in the range 235-240 K (0.77 katm) for THF and 240-252.5 K (1.86 katm) for Ar/Xe hydrate. The Z method was found to define the key thermodynamic states with high precision, although required long simulation times with these multicomponent molecular systems to ensure the complete melting required by the method. In contrast, the direct phase coexistence method did bracket the equilibrium temperature with little difficulty, but small thermodynamic driving forces close to phase equilibrium generated long-lived fluctuations, that obscured the precise value of phase coexistence conditions within the bracketed range.

Templates for wax deposition?

Molecular dynamics simulations have been used to study the behaviour of a liquid mixture of octacosane and heptane between two planar hematite surfaces; one of the surfaces was coated by a monolayer of an imidazoline-based corrosion inhibitor (CI). It was found that the octacosane could be inserted into the CI monolayer when it was aligned with the alkyl tails of the CIs, but the rate for such an insertion was slow. Potential of mean force calculations confirmed that there is a free energy barrier to insertion of octacosane into the CI film, and identified a secondary minimum about 13 A from the surface as a metastable intermediate for insertion. A much more rapid process was adsorption of the octacosane onto the exposed hematite (1012) surface, forming multiple layers and with a packing that was reminiscent of the octacosane crystal structure but with an orientation that matched the topology of the haematite surface.

Isomer separation and gas-phase configurations of organoruthenium anticancer complexes: ion mobility mass spectrometry and modeling.

We have used ion mobility-mass spectrometry combined with molecular modeling for the separation and configurational analysis of three low-molecular-weight isomeric organoruthenium anticancer complexes containing ortho-, meta-, or para-terphenyl arene ligands. The isomers were separated using ion mobility based on traveling-wave technology and the experimentally determined collision cross sections were compared to theoretical calculations. Excellent agreement was observed between the experimentally and theoretically derived measurements.

Gas hydrate nucleation and cage formation at a water/methane interface.

Nucleation of gas hydrates remains a poorly understood phenomenon, despite its importance as a critical step in understanding the performance and mode of action of low dosage hydrate inhibitors. We present here a detailed analysis of the structural and mechanistic processes by which gas hydrates nucleate in a molecular dynamics simulation of dissolved methane at a methane/water interface. It was found that hydrate initially nucleates into a phase consistent with none of the common bulk crystal structures, but containing structural units of all of them. The process of water cage formation has been found to correlate strongly with the collective arrangement of methane molecules.

Nucleation and control of clathrate hydrates: insights from simulation.

Clathrate hydrates are important in both industrial and geological settings. They give rise to many technological and environmental applications, including energy production, gas transport, global warming and CO2 capture and sequestration. In all of these applications there is a need to exert a high degree of control on the crystallisation process, either to promote or inhibit it according to the application. This crystallisation process involves the formation of a tetrahedral hydrogen bonding network (as occurs with ice), but is complicated by mass transport limitations due to the poor mixing of the common guest molecules, such as methane, and the water that forms the host lattice. The net effect is that the mechanisms for hydrate formation and growth are still poorly understood, with the consequence that development of additives to control nucleation and growth is still largely governed by trial-and-error approaches. In this paper we show how classical molecular dynamics simulations can be used to provide a direct simulation of the nucleation process for methane hydrate and consequently to allow direct simulation of the effect of additives on the nucleation and growth process. Data are presented for oligomers of PVP and compared with existing data for PDMAEMA. The results show that the two additives work by very different mechanisms, with PVP increasing the surface energy of the interfacial region and PDMAEMA adsorbing to the surface of hydrate nanocrystals. The surface energy effect is a mechanism that has not previously been considered for hydrate inhibitors.

Shape effects on the activity of synthetic major-groove binding ligands.

In this work we present the results of a molecular simulation study of two different tetracationic bis iron(II) supramolecular cylinders interacting with DNA. One cylinder has been shown to bind in the major groove of DNA and to induce dramatic coiling of the DNA; the second is a derivative of the first, with additional methyl groups attached so as to give a larger cylinder-radius. The simulations show that both cylinders bind strongly to the major groove of the DNA, and induce complex structural changes in A-T rich regions. Whereas the parent cylinder tends to bind along the major groove, the derivatised cylinder tends to twist so that only one end remains within the major groove. Both G-C rich and A-T rich binding sites for the derivatised cylinder are discussed.

Structure of anhydrous alkali-metal formates.

Single-crystal X-ray diffraction has yielded new crystal structures for cesium formate (CsOOCH) and rubidium formate (RbOOCH). The cesium formate structure has the same unit cell and space group as that published from powder X-ray diffraction data but differs radically in the placement and orientation of the formate ions. The new crystal structure has been successfully modeled with an empirical force field based on pair potentials, whereas it proved impossible to develop a force field that gave an adequate description of the powder structure. For rubidium formate, the gross structure is similar to that previously published, but the space group includes a mirror plane (Pbcm rather than Pbc2(1)). From this information, we have been able to analyze the effect of the cation size on the crystal structure for alkali-metal formates.