Reparameterization of Polarizable Force Fields for Studying Ion Transfer across Liquid-Liquid Interfaces.

We have developed a general scheme for refining classical polarizable molecular dynamics (MD) force fields that can accurately describe the molecular interactions in systems with liquid-liquid interfaces. While ab initio MD (AIMD) simulations can naturally describe molecular interactions, they are often so computationally expensive that simulating large system sizes and/or long time scales is usually infeasible. To resolve this, we parameterized efficient and accurate classical polarizable force fields that use AIMD reference data by minimizing both the relative entropy and the root mean squared deviation in atomic forces. We utilized our new multiscale models to study chloride ion transfer across the water-dichloromethane (DCM) interface with and without the tetraethylammonium cation as the phase-transfer catalyst. Our calculated free-energy barrier for the water-DCM interface is consistent with the other reported simulation results. We further analyzed the ion-transfer process by studying the hydration shell structures around the chloride ion and the ion-pair formation to better understand the mechanism. We observed that electronic polarizability is an important factor for the studied phase-transfer catalyst to lower the free-energy barrier of the ion transfer. Using the water-benzene interface system as an additional example, we show that our parameterization scheme provides a general route for modeling different liquid-liquid interface systems even when the experimental data or force field parameters are not readily available.

Site-Selective Tyrosine Reaction for Antibody-Cell Conjugation and Targeted Immunotherapy.

Targeted immunotherapies capitalize on the exceptional binding capabilities of antibodies to stimulate a host response that effectuates long-lived tumor destruction. One example is the conjugation of immunoglobulins (IgGs) to immune effector cells, which equips the cells with the ability to recognize and accurately kill malignant cells through a process called antibody-dependent cellular cytotoxicity (ADCC). In this study, a chemoenzymatic reaction is developed that specifically functionalizes a single tyrosine (Tyr, Y) residue, Y296, in the Fc domain of therapeutic IgGs. A one-pot reaction that combines the tyrosinase-catalyzed oxidation of tyrosine to o-quinone with a subsequent [3+2] photoaddition with vinyl ether is employed. This reaction installs fluorescent molecules or bioorthogonal groups at Y296 of IgGs or the C-terminal Y-tag of an engineered nanobody. The Tyr-specific reaction is utilized in constructing monofunctionalized antibody-drug conjugates (ADCs) and antibody/nanobody-conjugated effector cells, such as natural killer cells or macrophages. These results demonstrate the potential of site-selective antibody reactions for enhancing targeted cancer immunotherapy.

Trialkylphosphonium oxoborates as C(sp3)-H oxyanion holes and their application in catalytic chemoselective acetalization.

The use of trialkylphosphonium oxoborates (TOB) as catalysts is reported. The site-isolated borate counter anion in a TOB catalyst increases the availability of C(sp3)-H to interact with electron donor substrates. The catalytic protocol is applicable to a wide range of substrates in the acetalization reaction and provides excellent chemoselectivity in the acetalization over thioacetalization in the presence of alcohols and thiols, which is otherwise hard to achieve using typical acid catalysts. Experimental and computational studies revealed that the TOB catalysts have multiple preorganized C(sp3)-Hs that serve as a mimic of oxyanion holes, which can stabilize the oxyanion intermediates via multiple C(sp3)-H non-classical hydrogen bond interactions.

Temperature-Responsive Pickering Double Emulsions Stabilized by Binary Microgels.

Microgels are excellent emulsifiers that can self-assemble to reduce interfacial tension and form a steric barrier at an oil-water interface. Herein, we report a two-step emulsification approach to prepare oil-in-water-in-oil (O/W/O) Pickering double emulsions through the dispersion of microgels in two immiscible phases. The stabilization mechanism depends on the uneven distribution and adsorption of hydrophilic water-swollen microgels and hydrophobic octanol-swollen microgels on either outer water droplets or inner oil droplets. Our results reveal that binary microgels outperformed single microgels in terms of interfacial tension reduction and emulsion stabilization. Notably, the binary microgel-stabilized Pickering double emulsions show excellent temperature responsiveness owing to the intrinsic thermal sensitivity of microgels. Consequently, the selective and rapid release of encapsulated substances in different phases can be achieved through the adjustment of the ambient temperature.

Capturing coacervate formation and protein partition by molecular dynamics simulation.

Biomolecules localize and function in microenvironments where their local concentration, spatial organization, and biochemical reactivity are regulated. To compartmentalize and control the local properties of the native microenvironment, cellular mimics and artificial bioreactors have been developed to study the properties of membraneless organelles or mimic the bio-environment for life origin. Here, we carried out molecular dynamics simulation with the Martini 3.0 model to reproduce the experimental salt concentration and pH dependency of different complex coacervates. We showed that coacervates inside vesicles are able to change their shape. In addition, we used these coacervate systems to explore the partitioning of the ubiquitous cytoskeletal protein actin and found that actin spontaneously partitions to all the coacervate peripheries. Therefore, we believe that our study can provide a better understanding of the versatile coacervate platform, where biomolecules partition and gather to fulfill their biological duties.

Flexible Polarizable Water Model Parameterized via Gaussian Process Regression.

Water is one of the most common components in molecular dynamics (MD) simulations. Using Gaussian process regression for predicting the properties of a water model without the need of running a simulation whenever the parameters are changed, we obtained a flexible polarizable water model, named SWM4/Fw, that is able to reproduce many reference water properties. The added flexibility is critical for modeling chemical reactions in which chemical bonds can be stretched or even broken and for directly calculating vibrational spectra. In addition to being one of the few water models that are both flexible and polarizable, SWM4/Fw is also efficient thanks to the extended Lagrangian scheme with Drude oscillators. The overall accuracy is on par with or better than the related SWM4-NDP model.

A Catalyst-Controlled Enantiodivergent Bromolactonization.

A catalyst-controlled enantiodivergent bromolactonization of olefinic acids has been developed. Quinine-derived amino-amides bearing the same chiral core but different achiral aryl substituents were used as the catalysts. Switching the methoxy substituent in the aryl amide system from meta- to ortho-position results in a complete switch in asymmetric induction to afford the desired lactone in good enantioselectivity and yield. Mechanistic studies, including chemical experiments and density functional theory calculations, reveal that the differences in steric and electronic effects of the catalyst substituent alter the reaction mechanism.

Hindered Diffusion near Fluid-Solid Interfaces: Comparison of Molecular Dynamics to Continuum Hydrodynamics.

Studying the near-wall hindered diffusion of a particle suspended in a fluid is critical for understanding other more complex, confined systems. We provide a review of the previous experimental and simulation efforts trying to verify the classic calculations in hydrodynamics by Brenner and Faxén. We discuss some of the challenges of extracting the hindered diffusion constants from the mean squared displacements as often done in the literature. We demonstrate that the use of total force autocorrelation functions is a reliable alternative for calculating the diffusion constants without similar challenges for our molecular dynamics (MD) simulations. We find that the change in the diffusion constant in the perpendicular direction calculated in MD is roughly consistent with the hydrodynamic result by Brenner provided that they are normalized by the diffusion constant at the center between the two walls. However, the discrepancy grows large when the colloidal particle is very close to the wall where molecular details matter. Even though the agreement can be considerably improved when the attractions between the particles are made stronger to reduce slip to better fulfill the no-slip condition in MD, we report that there is an underlying difference between the range of the wall interactions with the colloidal particle predicted by MD and hydrodynamics.

Simulation study of the effects of phase separation on hydroxide solvation and transport in anion exchange membranes.

Anion exchange membranes (AEMs) can be cheaper alternatives than proton exchange membranes, but a key challenge for AEMs is to archive good ionic conductivity while maintaining mechanical strength. Diblock copolymers containing a mechanically strong hydrophobic block and an ion-conducting hydrophilic block have been shown to be viable solutions to this challenge. Using our recently developed reactive hydroxide model, we investigate the effects of block size on the hydroxide solvation and transport in a diblock copolymer (PPO-b-PVBTMA) in its highly hydrated state. Typically, both hydroxide and water diffusion constants decrease as the hydrophobic PPO block size increases. However, phase separation takes place above a certain mole ratio of hydrophobic PPO to hydrophilic PVBTMA blocks and we found it to effectively recover the diffusion constants. Extensive analyses reveal that morphological changes modulate the local environment for hydroxide and water transport and contribute to that recovery. The activation energy barriers for hydroxide and water diffusion show abrupt jumps at the same block ratios when such recovery effects begin to appear, suggesting transformation of the structure of water channels. Taking the advantages of partial phase separation can help optimize both ionic conductivity and mechanical strength of fuel cell membranes.

Dopamine-Mediated Assembly of Citrate-Capped Plasmonic Nanoparticles into Stable Core-Shell Nanoworms for Intracellular Applications.

Plasmonic nanochains, derived from the one-dimensional assembly of individual plasmonic nanoparticles (NPs), remain infrequently explored in biological investigations due to their limited colloidal stability, ineffective cellular uptake, and susceptibility to intracellular disassembly. We report the synthesis of polydopamine (PDA)-coated plasmonic "nanoworms" (NWs) by sonicating citrate-capped gold (Cit-Au) NPs in a concentrated dopamine (DA) solution under alkaline conditions. DA mediates the assembly of Cit-Au NPs into Au NWs within 1 min, and subsequent self-polymerization of DA for 60 min enables the growth of an outer conformal PDA shell that imparts stability to the inner Au NW structure in solution, yielding "core-shell" Au@PDA NWs with predominantly 4-5 Au cores per worm. Our method supports the preparation of monometallic Au@PDA NWs with different core sizes and bimetallic PDA-coated NWs with Au and silver cores. The protonated primary amine and catechol groups of DA, with their ability to interact with Cit anions via hydrogen bonding and electrostatic attraction, are critical to assembly. When compared to unassembled PDA-coated Au NPs, our Au@PDA NWs scatter visible light and absorb near-infrared light more intensely and enter HeLa cancer cells more abundantly. Au@PDA NWs cross the cell membrane as intact entities primarily via macropinocytosis, mostly retain their inner NW structure and outer PDA shell inside the cell for 24 h, and do not induce noticeable cytotoxicity. We showcase three intracellular applications of Au@PDA NWs, including label-free dark-field scattering cell imaging, delivery of water-insoluble cargos without pronounced localization in acidic compartments, and photothermal killing of cancer cells.

Patchy colloidal particles at the fluid-fluid interface.

Colloidal particles have significantly different characteristics when they are at interfaces from when they are in the bulk. In this study, we applied Monte Carlo simulations to investigate the stability and dynamics of smooth patchy particles and rough patchy particles near or at the fluid-fluid interface. By adjusting the surface area ratio of the two faces of a smooth Janus particle, we show how its stability, in terms of free energy, in either side of the interface can be tuned relative to the smooth homogeneous particle. We demonstrate how roughness can affect the stability and the orientation of a colloidal particle. Moreover, position-dependent diffusion constants in directions parallel and perpendicular to the interface are calculated for the colloidal particles as a function of distance from the interface. We report drastic slowdowns in the perpendicular diffusivity (and less severe slowdowns for the parallel diffusivity) for all the colloidal particles when they approach the fluid-fluid interface. While such a slowdown is well-known for the fluid-solid interface in the literature in terms of frictional force in hydrodynamics, why this happens for the fluid-fluid interface has not been adequately discussed. We provide evidence for the decrease in terms of discrepancy in the fluid density that leads to depletion forces.

Applications of Selenonium Cations as Lewis Acids in Organocatalytic Reactions.

The use of trisubstituted selenonium salts as organic Lewis acids in electrophilic halogenation and aldol-type reactions has been developed. The substrate scope is broad. The reaction conditions are mild and compatible with various functionalities. This study opens a new avenue for the development of nonmetallic Lewis acid catalysis.

Free energy study of H2O, N2O5, SO2, and O3 gas sorption by water droplets/slabs.

Understanding gas sorption by water in the atmosphere is an active research area because the gases can significantly alter the radiation and chemical properties of the atmosphere. We attempt to elucidate the molecular details of the gas sorption of water and three common atmospheric gases (N2O5, SO2, and O3) by water droplets/slabs in molecular dynamics simulations. The system size effects are investigated, and we show that the calculated solvation free energy decreases linearly as a function of the reciprocal of the number of water molecules from 1/215 to 1/1000 in both the slab and the droplet systems. By analyzing the infinitely large system size limit by extrapolation, we find that all our droplet results are more accurate than the slab results when compared to the experimental values. We also show how the choice of restraints in umbrella sampling can affect the sampling efficiency for the droplet systems. The free energy changes were decomposed into the energetic ΔU and entropic -TΔS contributions to reveal the molecular details of the gas sorption processes. By further decomposing ΔU into Lennard-Jones and Coulombic interactions, we observe that the ΔU trends are primarily determined by local effects due to the size of the gas molecule, charge distribution, and solvation structure around the gas molecule. Moreover, we find that there is a strong correlation between the change in the entropic contribution and the mean residence time of water, which is spatially nonlocal and related to the mobility of water.

Role of Presolvation and Anharmonicity in Aqueous Phase Hydrated Proton Solvation and Transport.

Results from condensed phase ab initio molecular dynamics (AIMD) simulations suggest a proton transfer reaction is facilitated by "presolvation" in which the hydronium is transiently solvated by four water molecules, similar to the typical solvation structure of water, by accepting a weak hydrogen bond from the fourth water molecule. A new version 3.2 multistate empirical valence bond (MS-EVB 3.2) model for the hydrated excess proton incorporating this presolvation behavior is therefore developed. The classical MS-EVB simulations show similar structural properties as those of the previous model but with significantly improved diffusive behavior. The inclusion of nuclear quantum effects in the MS-EVB also provides an even better description of the proton diffusion rate. To quantify the influence of anharmonicity, a second model (aMS-EVB 3.2) is developed using the anharmonic aSPC/Fw water model, which provides similar structural properties but improved spectroscopic responses at high frequencies.

Hydroxide Solvation and Transport in Anion Exchange Membranes.

Understanding hydroxide solvation and transport in anion exchange membranes (AEMs) can provide important insight into the design principles of these new membranes. To accurately model hydroxide solvation and transport, we developed a new multiscale reactive molecular dynamics model for hydroxide in aqueous solution, which was then subsequently modified for an AEM material. With this model, we investigated the hydroxide solvation structure and transport mechanism in the membrane. We found that a relatively even separation of the rigid side chains produces a continuous overlapping region for hydroxide transport that is made up of the first hydration shell of the tethered cationic groups. Our results show that hydroxide has a significant preference for this overlapping region, transporting through it and between the AEM side chains with substantial contributions from both vehicular (standard diffusion) and Grotthuss (proton hopping) mechanisms. Comparison of the AEM with common proton exchange membranes (PEMs) showed that the excess charge is less delocalized in the AEM than the PEMs, which is correlated with a higher free energy barrier for proton transfer reactions. The vehicular mechanism also contributes considerably more than the Grotthuss mechanism for hydroxide transport in the AEM, while our previous studies of PEM systems showed a larger contribution from the Grotthuss mechanism than the vehicular mechanism for proton transport. The activation energy barrier for hydroxide diffusion in the AEM is greater than that for proton diffusion in PEMs, implying a more significant enhancement of ion transport in the AEM at elevated temperatures.

Propensity of Hydrated Excess Protons and Hydroxide Anions for the Air-Water Interface.

Significant effort has been undertaken to better understand the molecular details governing the propensity of ions for the air-water interface. Facilitated by computationally efficient reactive molecular dynamics simulations, new and statistically conclusive molecular-scale results on the affinity of the hydrated excess proton and hydroxide anion for the air-water interface are presented. These simulations capture the dynamic bond breaking and formation processes (charge defect delocalization) that are important for correctly describing the solvation and transport of these complex species. The excess proton is found to be attracted to the interface, which is correlated with a favorable enthalpic contribution and consistent with reducing the disruption in the hydrogen bond network caused by the ion complex. However, a recent refinement of the underlying reactive potential energy function for the hydrated excess proton shows the interfacial attraction to be weaker, albeit nonzero, a result that is consistent with the experimental surface tension measurements. The influence of a weak hydrogen bond donated from water to the protonated oxygen, recently found to play an important role in excess hydrated proton transport in bulk water, is seen to also be important for this study. In contrast, the hydroxide ion is found to be repelled from the air-water interface. This repulsion is characterized by a reduction of the energetically favorable ion-water interactions, which creates an enthalpic penalty as the ion approaches the interface. Finally, we find that the fluctuation in the coordination number around water sheds new light on the observed entropic trends for both ions.

Ion mixing, hydration, and transport in aqueous ionic systems.

The enhancement effect on the ion mobility of fluoride (and that of chloride) in a polycationic system, as the chloride content increases, is shown to also exist in other more simple ionic systems with cations such as the cesium ion and an organic ammonium ion. As the chloride content increases, in addition to the finding that there is more unbound water associated with the cation, we also observe that the average lifetime of a hydrogen bond decreases. This change to the hydrogen bonds is correlated to significant changes to both the structural and dynamical properties of water. The more disordered water structure and faster water dynamics are hypothesized to be also responsible for the enhanced ion mobilities. Furthermore, when either the chloride content or hydration level is changed, the self-diffusion constant of each co-ion changes by almost the same factor, implying the existence of a single universal transport mechanism that determines ion mobilities.

An analysis of hydrated proton diffusion in ab initio molecular dynamics.

A detailed understanding of the inherently multiscale proton transport process raises a number of scientifically challenging questions. For example, there remain many (partially addressed) questions on the molecular mechanism for long-range proton migration and the potential for the formation of long-lived traps giving rise to burst-and-rest proton dynamics. Using results from a sizeable collection of ab initio molecular dynamics (AIMD) simulations (totaling ∼2.7 ns) with various density functional approximations (Becke-Lee-Yang-Parr (BLYP), BLYP-D3, Hamprecht-Cohen-Tozer-Handy, B3LYP) and temperatures (300-330 K), equilibrium and dynamical properties of one excess proton and 128 water molecules are studied. Two features in particular (concerted hops and weak hydrogen-bond donors) are investigated to identify modes in the system that are strongly correlated with the onset of periods of burst-and-rest dynamics. The question of concerted hops seeks to identify those time scales over which long-range proton transport can be classified as a series of sequential water hopping events or as a near-simultaneous concerted process along compressed water wires. The coupling of the observed burst-and-rest dynamics with motions of a fourth neighboring water molecule (a weak hydrogen-bond donor) solvating the protonated water molecule is also investigated. The presence (absence) of hydrogen bonds involving this fourth water molecule before and after successful proton hopping events is found to be strongly correlated with periods of burst (rest) dynamics (and consistent with pre-solvation concepts). By analyzing several realizations of the AIMD trajectories on the 100-ps time scale, convergence of statistics can be assessed. For instance, it was observed that the probability for a fourth water molecule to approach the hydronium, if not already proximal at the beginning of the lifetime of the hydronium, is very low, indicative of the formation of stable void regions. Furthermore, the correlations of the neighboring water atoms are identified as the fourth water approaches the hydronium. Finally, the temperature effects on structural and dynamical properties are studied.

Modified scaling principle for rotational relaxation in a model for suspensions of rigid rods.

We have performed simulations of the model of infinitely thin rigid rods undergoing rotational and translational diffusion, subject to the restriction that no two rods can cross one another, for various concentrations well into the semidilute regime. We used a modification of the algorithm of Doi et al. [J. Phys. Soc. Jpn. 53, 3000 (1984)] that simulates diffusive dynamics using a Monte Carlo method and a nonzero time step. In the limit of zero time step, this algorithm is an exact description of diffusive dynamics subject to the noncrossing restriction. For a wide range of concentrations in the semidilute regime, we report values of the long time rotational diffusion constant of the rods, extrapolated to the limit of zero time step, for various sets of values of the infinite dilution (bare) diffusion constants. These results are compared with the results of a previous simulation of the model by Doi et al. and of previous simulations of rods with finite aspect ratio by Fixman and by Cobb and Butler that had been extrapolated to the limit of infinitely thin rods. The predictions of the Doi-Edwards (DE) scaling law do not hold for this model for the concentrations studied. The simulation data for the model display two deviations from the predictions of the DE theory that have been observed in experimental systems in the semidilute regime, namely, the very slow approach toward DE scaling behavior as the concentration is increased and the large value of the prefactor in the DE scaling law. We present a modified scaling principle for this model that is consistent with the simulation results for a broad range of concentrations in the semidilute regime. The modified scaling principle takes into account two physical effects, which we call "leakage" and "drift," that were found to be important for the transport properties of a simpler model of nonrotating rods on a lattice [Y.-L. S. Tse and H. C. Andersen, J. Chem. Phys. 136, 024904 (2012)].

A lattice model of the translational dynamics of nonrotating rigid rods.

We present a lattice model of oriented, nonrotating, rigid rods in three dimensions with random walk dynamics, computer simulation results for the model, and a theory for the translational diffusion constant of the rods in the perpendicular direction, D(⊥), in the semidilute regime. The theory is based on the "tube model" of Doi-Edwards (DE) theory for the rotational diffusion constant of rods that can both translate and rotate in continuous space. The theory predicts that D(⊥) is proportional to (νL(3))(-2), where ν is the concentration of rods and L is the length of the rods, which is analogous to the Doi-Edwards scaling law for rotational diffusion. The simulations find that, as νL(3) is increased, the approach to the limit of DE scaling is slow, and the -2 power in the DE scaling law is never quite achieved even at the highest concentration (νL(3) = 200) simulated. We formulate a quantitative theory for the prefactor in the scaling relationship using only DE ideas, but it predicts a proportionality constant that is much too small. To explain this discrepancy, we modify the DE approach to obtain a more accurate estimate of the average tube radius and take into account effects of perpendicular motion of rods that are not included in the original DE theory. With these changes, the theory predicts values of D(⊥) that are in much better agreement with the simulations. We propose a new scaling relationship that fits the data very well. This relationship suggests that the DE scaling law is the correct description of the scaling for infinitely thin rods only in the limit of infinite concentration, and that corrections to the DE scaling law because of finite concentration are significant even at concentrations that are well inside the semidilute regime. The implications of these results for the DE theory of rotating rods are discussed.