Ravi Radhakrishnan

Phase separation in confined systems

We review the current state of knowledge of phase separation and phase equilibria in porous materials. Our emphasis is on fundamental studies of simple fluids (composed of small, neutral molecules) and well-characterized materials. While theoretical and molecular simulation studies are stressed, we also survey experimental investigations that are fundamental in nature. Following a brief survey of the most useful theoretical and simulation methods, we describe the nature of gas‐liquid (capillary condensation), layering, liquid‐liquid and freezing/melting transitions. In each case studies for simple pore geometries, and also more complex ones where available, are discussed. While a reasonably good understanding is available for phase equilibria of pure adsorbates in simple pore geometries, there is a need to extend the models to more complex pore geometries that include effects of chemical and geometrical heterogeneity and connectivity. In addition, with the exception of liquid‐liquid equilibria, little work has been done so far on phase separation for mixtures in porous media.

Effects of confinement on freezing and melting

We present a review of experimental, theoretical, and molecular simulation studies of confinement effects on freezing and melting. We consider both simple and more complex adsorbates that are confined in various environments (slit or cylindrical pores and also disordered porous materials). The most commonly used molecular simulation, theoretical and experimental methods are first presented. We also provide a brief description of the most widely used porous materials. The current state of knowledge on the effects of confinement on structure and freezing temperature, and the appearance of new surface-driven and confinement-driven phases are then discussed. We also address how confinement affects the glass transition.

ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation

ErbB3/HER3 is one of four members of the human epidermal growth factor receptor (EGFR/HER) or ErbB receptor tyrosine kinase family. ErbB3 binds neuregulins via its extracellular region and signals primarily by heterodimerizing with ErbB2/HER2/Neu. A recently appreciated role for ErbB3 in resistance of tumor cells to EGFR/ErbB2-targeted therapeutics has made it a focus of attention. However, efforts to inactivate ErbB3 therapeutically in parallel with other ErbB receptors are challenging because its intracellular kinase domain is thought to be an inactive pseudokinase that lacks several key conserved (and catalytically important) residues—including the catalytic base aspartate. We report here that, despite these sequence alterations, ErbB3 retains sufficient kinase activity to robustly trans-autophosphorylate its intracellular region—although it is substantially less active than EGFR and does not phosphorylate exogenous peptides. The ErbB3 kinase domain binds ATP with a Kd of approximately 1.1 μM. We describe a crystal structure of ErbB3 kinase bound to an ATP analogue, which resembles the inactive EGFR and ErbB4 kinase domains (but with a shortened αC-helix). Whereas mutations that destabilize this configuration activate EGFR and ErbB4 (and promote EGFR-dependent lung cancers), a similar mutation conversely inactivates ErbB3. Using quantum mechanics/molecular mechanics simulations, we delineate a reaction pathway for ErbB3-catalyzed phosphoryl transfer that does not require the conserved catalytic base and can be catalyzed by the “inactive-like” configuration observed crystallographically. These findings suggest that ErbB3 kinase activity within receptor dimers may be crucial for signaling and could represent an important therapeutic target.

A new approach for studying nucleation phenomena using molecular simulations: Application to CO2 hydrate clathrates

We use an order-parameter formulation, in conjunction with non-Boltzmann sampling to study the nucleation of clathrate hydrates from water–CO2 mixtures, using computer simulations. A set of order parameters are defined: Φigg (i=1,2,…,n and gg for guest–guest), which characterize the spatial and orientational order of the CO2 molecules, and Φihh (hh for host–host), which govern the ordering of the water molecules. These are bond-orientational order parameters based on the average geometrical distribution of nearest-neighbor bonds. The free-energy hypersurface as a function of the order parameters is calculated using the Landau–Ginzburg approach. The critical cluster size that leads to the nucleation of the clathrate phase is determined accurately by analyzing the free energy surface. We find that the nucleation proceeds via “the local structuring mechanism,” i.e., a thermal fluctuation causing the local ordering of CO2 molecules leads to the nucleation of the clathrate, and not by the current conceptual pi...

Effect of the fluid-wall interaction on freezing of confined fluids: Toward the development of a global phase diagram

We report molecular simulation studies of the freezing behavior of fluids in nano-porous media. The effect of confinement is to induce spatial constraints as well as energetic heterogeneity on the confined fluid, thereby altering the bulk phase behavior drastically. We consider the effect of the fluid-wall interaction energy on the shift of the freezing temperature and on the fluid structure, using a novel approach to calculate the free energy surface based on Landau theory and order parameter formulation. Corresponding states theory is then used to map out the global freezing behavior of a Lennard-Jones (LJ) fluid in model slit-shaped pores of varying fluid-wall interaction strengths. Using LJ parameters fitted to thermophysical property behavior, we predict the qualitative freezing behavior for a variety of fluids and nano-porous materials, based on a global freezing diagram. We have attempted to verify these predictions by comparing with experimental data for several systems, and show that in these cas...

Global phase diagrams for freezing in porous media

Using molecular simulations and free energy calculations based on Landau theory, we show that freezing/melting behavior of fluids of small molecules in pores of simple geometry can be understood in terms of two main parameters: the pore width H* ~expressed as a multiple of the diameter of the fluid molecule ! and a parameter a that measures the ratio of the fluid-wall to the fluid‐fluid attractive interaction. The value of the a parameter determines the qualitative nature of the freezing behavior, for example, the direction of change in the freezing temperature and the presence or absence of new phases. For slit-shaped pores, larger a values lead to an increase in the freezing temperature of the confined fluid, and to the presence of a hexatic phase. For pores that accommodate three or more layers of adsorbate molecules several kinds of contact layer phase ~inhomogeneous phases in which the contact layer has a different structure than the inner layers! are observed. Smaller a values lead to a decrease in the freezing temperature. The parameter H* determines the magnitude of shift in the freezing temperature, and can also affect the presence of some of the new phases. Results are presented as plots of transition temperature vs a for a particular pore width. Experimental results are also presented for a variety of adsorbates in activated carbon fibers~ACF! covering a wide range of a values; the ACF have slit-shaped pores with average pore width 1.2 nm. The experimental and simulation results show qualitative agreement.

FREEZING OF SIMPLE FLUIDS IN MICROPOROUS ACTIVATED CARBON FIBERS : COMPARISON OF SIMULATION AND EXPERIMENT

We study the freezing of CCl4 in microporous activated carbon fibers (ACF), using Monte Carlo simulation and differential scanning calorimetry (DSC). Microporous activated carbon fibers are well characterized porous materials, having slit-shaped pores due to the voids formed between graphitic basal planes. They serve as highly attractive adsorbents for simple nonpolar molecules, the adsorbent–adsorbate interaction being mostly dispersive (of the van der Waals-type). Recent molecular simulation studies have predicted an upward shift in the freezing temperature (ΔTf=Tf,pore−Tf,bulk>0) for simple fluids confined in such highly attractive carbon slit pores. Our DSC experiments verify these predictions about the increase in Tf. The results also indicate significant deviation from the prediction of ΔTf based on the Gibbs–Thomson equation (simple capillary theory). We employ a recently developed free energy method to calculate the exact freezing temperature in these confined systems using molecular simulation, i...

Free energy studies of freezing in slit pores: an order-parameter approach using Monte Carlo simulation

We report a molecular simulation study of freezing transitions for simple fluids in narrow slit pores. A major stumbling block in previous studies of freezing in pores has been the lack of any method for calculating the free energy difference between the confined solid and liquid phases. Conventional thermodynamic integration methods often fail for confined systems, due to the difficulty in choosing a suitable path of integration. We use a different approach that involves calculating the Landau free energy as a function of a suitable order parameter, using the grand canonical Monte Carlo simulation method. The grand free energy for each phase can then be obtained by one-dimensional integration of the Landau free energy over the order parameter. These calculations are carried out for two types of wall—fluid interaction, a hard wall and a strongly attractive wall modelled on carbon. The grand free energy results for both cases clearly indicate a first order fluid to solid transition. In the case of the attr...

ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma

Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples--at three hot spots and 13 minor sites--and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.

Melting/freezing behavior of a fluid confined in porous glasses and MCM-41: Dielectric spectroscopy and molecular simulation

We report both experimental measurements and molecular simulations of the melting and freezing behavior of fluids in nanoporous media. The experimental studies are for nitrobenzene in the silica-based pores of controlled pore glass, Vycor, and MCM-41. Dielectric relaxation spectroscopy is used to determine melting points and the orientational relaxation times of the nitrobenzene molecules in the bulk and the confined phase. Monte Carlo simulations, together with a bond orientational order parameter method, are used to determine the melting point and fluid structure inside cylindrical pores modeled on silica. Qualitative comparison between experiment and simulation are made for the shift in the freezing temperatures and the structure of confined phases. From both the experiments and the simulations, it is found that the confined fluid freezes into a single crystalline structure for average pore diameters greater than 20σ, where σ is the diameter of the fluid molecule. For average pore sizes between 20σ and...