Insights into the mechanism of peptide fibril growth on gold surface.

Understanding the formation of ß-fibrils over the gold surface is of paramount interest in nano-bio-medicinal Chemistry. The intricate mechanism of self-assembly of neurofibrillogenic peptides and their growth over the gold surface remains elusive, as experiments are limited in unveiling the microscopic dynamic details, in particular, at the early stage of the peptide aggregation. In this work, we carried out equilibrium molecular dynamics and enhanced sampling simulations to elucidate the underlying mechanism of the growth of an amyloid-forming sequence of tau fragments over the gold surface. Our results disclose that the collective intermolecular interactions between the peptide chains and peptides with the gold surface facilitate the peptide adsorption, followed by integration, finally leading to the fibril formation.

Visible Light-Promoted Regioselective Benzannulation of Vinyl Sulfoxonium Ylides with Ynoates.

Herein, we report a highly regioselective [4 + 2]-annulation of vinyl sulfoxonium ylides with ynoates under light-mediated conditions. The reaction proceeds through the new dienyl sulfoxonium ylide, which undergoes photolysis under blue light irradiation to give highly substituted naphthalene scaffolds. The method presented here operates at room temperature and does not require the addition of an external photosensitizer. The in situ-generated dienyl sulfoxonium ylide absorbs light and acts as a photosensitizer for the formation of arenes. The synthetic potential of these benzannulations was further illustrated by various synthetic transformations and a scale-up reaction. Moreover, control experiments and quantum chemical calculations reveal the mechanistic details of the developed reaction.

Carbene-mediated stereoselective olefination of vinyl sulfoxonium ylides with diazo compounds and acetals.

The development of stereoselective olefination using sulfur ylide-derived vinyl carbenes with diazo esters and acetals is reported. Both reactions proceed through nucleophilic addition to electrophiles at the γ-position of an in situ-generated 2-alkoxy furan intermediate. The synthetic utility of the developed method is demonstrated by the total synthesis of rubrolide E. Detailed mechanistic investigations and quantum chemical calculations provide insight into the reaction mechanism.

Electrostatic-Driven Self-Assembly of Janus-like Monolayer-Protected Metal Nanoclusters.

The generation of controlled microstructures of functionalized nanoparticles has been a crucial challenge in nanoscience and nanotechnology. Efforts have been made to tune ligand charge states that can affect the aggregation propensity and modulate the self-assembled structures. In this work, we modeled zwitterionic Janus-like monolayer ligand-protected metal nanoclusters (J-MPCs) and studied their self-assembly using atomistic molecular dynamics and on-the-fly probability-based enhanced sampling simulations. The oppositely charged ligand functionalization on two hemispheres of a J-MPC elicits asymmetric solvation, primarily driven by distinctive hydrogen bonding patterns in the ligand-solvent interactions. Electrostatic interactions between the oppositely charged residues in J-MPCs guide the formation of one-dimensional and ring-like self-assembled superstructures with molecular dipoles oriented in specific patterns. The pertinent atomistic insights into the intermolecular interactions governing the self-assembled structures of zwitterionic J-MPCs obtained from this work can be used to design a general strategy to create tunable microstructures of charged MPCs.

Insights into the Interactions of Peptides with Monolayer-Protected Metal Nanoclusters.

Monolayer-protected atomically precise metal nanoclusters (MPCs) have potential applications in catalysis, imaging, and drug delivery. Understanding their interactions with biomolecules such as peptides is of paramount interest for their use in cell imaging and drug delivery. Here we have carried out atomistic molecular dynamics simulations to investigate the interactions between MPCs and an anticancer peptide, melittin. Melittin gets attached to the MPCs surface by the formation of multiple hydrogen bonds between its amino acid residues with MPCs ligands. Additionally, the positively charged Lys, Arg, and peptide's N-terminal strongly anchor the peptide to the MPC metal surface, providing extra stabilization.

Elucidating the Role of Atomically Dilute Copper Centers Impregnating a Phosphamide Polymer for the Preferential Hydrogen Evolution Reaction over CO2 Reduction.

Organic polymers have attracted considerable interest in designing a multifunctional electrocatalyst. However, the inferior electro-conductivity of such metal-free polymers is often regarded as a shortcoming. Herein, a nitrogen- and phosphorus-rich polymer with phosphamide functionality (PAP) in the repeating unit has been synthesized from diaminopyridine (DAP) and phenylphosphonic dichloride (PPDC) precursors. The presence of phosphamide oxygen and pyridine nitrogen in the repeating unit of PAP leads to the coordination of the CuII ion and the incorporation of 3.29 wt % in the polymer matrix (Cu30@PAP) when copper salt is used to impregnate the polymer. Combined with a spectroscopic, microscopic, and DFT study, the coordination and geometry of copper in the PAP matrix has been established to be a distorted square planar CuII in a N2O2 ligand environment where phosphamide oxygen and pyridine nitrogen of the PAP coordinate to the metal center. The copper incorporation in the PAP modulates its electrocatalytic activity. On the glassy carbon electrode, PAP shows inferior activity toward the hydrogen evolution reaction (HER) in 0.5 M H2SO4 while 3 wt % copper incorporation (Cu30@PAP) significantly improves the HER performance with an overpotential of 114 mV at 10 mA cm-2. The notable electrochemical activity with Cu30@PAP occurs due to the impregnation of Cu(II) in PAP, improved electro-kinetics, and better charge transfer resistance (Rct). When changing the electrolyte from H2SO4 to CO2-saturated bicarbonate solution at nearly neutral pH, PAP shows HER as the dominant pathway along with the partial reduction of CO2 to formate. Moreover, the use of Cu30@PAP as an electrolcatalyst could not alter the predominant HER path, and only 20% Faradaic efficiency for the CO2 reduced products has been achieved. Post-chronoamperometric characterization of the recovered catalyst suggests an unaltered valence state of the copper ion and the intact chemical structure of PAP. DFT studies unraveled that the copper sites of Cu30@PAP promote water adsorption while phosphamide-NH of the PAP can weakly hold the CO2 adduct via a hydrogen bonding interaction. A detailed calculation has pointed out that the tetra-coordinated copper centers present in the PAP frame are the reactive sites and that the formation of the [CuI-H] intermediate is the rate-limiting step for both HER and its competitive side reaction, i.e., CO2 reduction to formate or CO formation. The high proton concentration in the electrolyte of pH < 7 leads to HER as the predominant pathway. This combined experimental and theoretical study has highlighted the crucial role of copper sites in electrocatalysis, emphasizing the plausible reason for electrocatalytic selectivity.

Divergent Approach to Highly Substituted Arenes via [3 + 3] Annulation of Vinyl Sulfoxonium Ylides with Ynones.

Herein, we report the divergent benzannulation for highly substituted arenes using vinyl sulfoxonium ylides and ynones. The addition of ynone at the γ-position of vinyl sulfoxonium ylides leads to dienyl sulfoxonium ylide that can undergo selective annulation under different conditions to give m-terphenyls and parabens. Moreover, control experiments and quantum chemical calculations reveal two distinct reaction mechanisms for both annulations.

Synthesis and Applications of π-Conjugation-Extended Vinyl Sulfoxonium Ylides.

Herein, we report the synthesis of π-conjugation-extended vinyl sulfoxonium ylides from vinyl sulfoxonium ylide and electron-deficient alkynes. The new dienoate ylides are used in various transformations, such as X-H (X = S, O) insertion, halogenation, carbene-mediated transformation, and radical-mediated reductions to obtain a variety of conjugated dienoates.

Thermodynamic Window for Size-Controlled Pore Formation in Graphene for Large-Scale Molecular Sieves.

Nanopores in graphene monolayers are a promising option for molecular separation applications, such as desalination and carbon capture. Graphene's atomic thickness allows for an optimal balance between molecular selectivity and permeability, while its chemical stability and robust mechanical properties make it appealing for a wide range of commercial applications. However, scaling to large areas with controlled pore size distribution is an open challenge in ultrathin membranes. Here, using first-principles calculations, we identify a suitable thermodynamic window in a chemical vapor deposition system for directly growing graphene monolayers with a controlled pore size distribution. As an example, our calculations show that a postgrowth annealing step with a supersaturation range of 19.7-25 kJ/mol at 1000 K results in the creation of a controllable pore density at graphene grain boundaries, with pore sizes falling within the range of 5-8 Å. Such pores isolate hydrated Cl ions from water molecules, effectively desalinating seawater. Thus, it allows the design of targeted synthesis of large-scale 2D layers for membrane applications.

Cu(I)/N,N-Imine Ligand Catalyzed C(sp3)-C(sp) Coupling of Alkyl Bromides with Alkynes: Scope and Mechanistic Investigation.

We have developed an efficient Cu/N,N-bidentate imine ligand catalytic system for C(sp3)-C(sp) coupling to obtain internal alkynes, di/trisubstituted allenes and strained bridged cyclic lactams in moderate to excellent yields from readily available alkyl(benzyl) bromides in one-pot transformation. Density Functional Theory (DFT) assisted mechanistic study along with control experiments support the involvement of bialkynylated copper species which undergo single electron transfer (SET) with alkyl halides to generate radical intermediate in the reaction. The N,N-bidentate imine ligand plays a vital role in stabilization of intermediate copper complex and facilitates the product formation.

Understanding Molecular Aggregation of Ligand-Protected Atomically-Precise Metal Nanoclusters.

Monolayer-protected atomically precise nanoclusters (MPCs) are an important class of molecules due to their unique structural features and diverse applications, including bioimaging, sensors, and drug carriers. Understanding the atomistic and dynamical details of their self-assembly process is crucial for designing system-specific applications. Here, we applied molecular dynamics and on-the-fly probability-based enhanced sampling simulations to study the aggregation of Au25(pMBA)18 MPCs in aqueous and methanol solutions. The MPCs interact via both hydrogen bonds and π-stacks between the aromatic ligands to form stable dimers, oligomers, and crystals. The dimerization free energy profiles reveal a pivotal role of the ligand charged state and solvent mediating the molecular aggregation. Furthermore, MPCs' ligands exhibit suppressed conformational flexibility in the solid phase due to facile intercluster hydrogen bonds and π-stacks. Our work provides unprecedented molecular-level dynamical details of the aggregation process and conformational dynamics of MPCs ligands in solution and crystalline phases.

Expanded triazolophanes: a topological analysis of vesicular assembly.

Triazolophanes with larger ring sizes such as 40- and 42- were designed and synthesized. Ultramicroscopic studies on a variety of expanded triazolophanes and larger acyclic systems revealed vesicular self-assembly. The role of molecular topology on vesicular assembly was systematically investigated by studying a series of molecules with increasing curvature.

Cyclic(alkyl)(amino)carbene (CAAC)- and bicyclic (alkyl)(amino)carbene (BICAAC)-derived glyoxal radical cations with excellent stability.

Examples of air- and water-stable main-group radicals are scarce in the literature due to the higher reactivity of radical compounds as well as several synthetic challenges. Herein, we report two stable structurally characterized glyoxal radical cations (1˙+ and 2˙+) stabilized by cyclic(alkyl)(amino)carbene (CAAC) and bicyclic (alkyl)(amino)carbene (BICAAC), respectively. Both 1˙+ and 2˙+ are stable under harsh conditions such as strong acids, bases, mild oxidizing agents, and reducing agents, as well as towards bovine serum. Radical (2˙+) represents the first isolated radical stabilized by a BICAAC ligand.

Non-Equilibrium Modeling of Concentration-Driven processes with Constant Chemical Potential Molecular Dynamics Simulations.

ConspectusConcentration-driven processes in solution, i.e., phenomena that are sustained by persistent concentration gradients, such as crystallization and surface adsorption, are fundamental chemical processes. Understanding such phenomena is crucial for countless applications, from pharmaceuticals to biotechnology. Molecular dynamics (MD), both in- and out-of-equilibrium, plays an essential role in the current understanding of concentration-driven processes. Computational costs, however, impose drastic limitations on the accessible scale of simulated systems, hampering the effective study of such phenomena. In particular, due to these size limitations, closed system MD of concentration-driven processes is affected by solution depletion/enrichment that unavoidably impacts the dynamics of the chemical phenomena under study. As a notable example, in simulations of crystallization from solution, the transfer of monomers between the liquid and crystal phases results in a gradual depletion/enrichment of solution concentration, altering the driving force for phase transition. In contrast, this effect is negligible in experiments, given the macroscopic size of the solution volume. Because of these limitations, accurate MD characterization of concentration-driven phenomena has proven to be a long-standing simulation challenge. While disparate equilibrium and nonequilibrium simulation strategies have been proposed to address the study of such processes, the methodologies are in continuous development.In this context, a novel simulation technique named constant chemical potential molecular dynamics (CµMD) was recently proposed. CµMD employs properly designed, concentration-dependent external forces that regulate the flux of solute species between selected subregions of the simulation volume. This enables simulations of systems under a constant chemical drive in an efficient and straightforward way. The CµMD scheme was originally applied to the case of crystal growth from solution and then extended to the simulation of various physicochemical processes, resulting in new variants of the method. This Account illustrates the CµMD method and the key advances enabled by it in the framework of in silico chemistry. We review results obtained in crystallization studies, where CµMD allows growth rate calculations and equilibrium shape predictions, and in adsorption studies, where adsorption thermodynamics on porous or solid surfaces was correctly characterized via CµMD. Furthermore, we will discuss the application of CµMD variants to simulate permeation through porous materials, solution separation, and nucleation upon fixed concentration gradients. While presenting the numerous applications of the method, we provide an original and comprehensive assessment of concentration-driven simulations using CµMD. To this end, we also shed light on the theoretical and technical foundations of CµMD, underlining the novelty and specificity of the method with respect to existing techniques while stressing its current limitations. Overall, the application of CµMD to a diverse range of fields provides new insight into many physicochemical processes, the in silico study of which has been hitherto limited by finite-size effects. In this context, CµMD stands out as a general-purpose method that promises to be an invaluable simulation tool for studying molecular-scale concentration-driven phenomena.

Collective Variables for Crystallization Simulations-from Early Developments to Recent Advances.

Crystallization is an important physicochemical process which has relevance in material science, biology, and the environment. Decades of experimental and theoretical efforts have been made to understand this fundamental symmetry-breaking transition. While experiments provide equilibrium structures and shapes of crystals, they are limited to unraveling how molecules aggregate to form crystal nuclei that subsequently transform into bulk crystals. Computer simulations, mainly molecular dynamics (MD), can provide such microscopic details during the early stage of a crystallization event. Crystallization is a rare event that takes place in time scales much longer than a typical equilibrium MD simulation can sample. This inadequate sampling of the MD method can be easily circumvented by the use of enhanced sampling (ES) simulations. In most of the ES methods, the fluctuations of a system's slow degrees of freedom, called collective variables (CVs), are enhanced by applying a bias potential. This transforms the system from one state to the other within a short time scale. The most crucial part of such CV-based ES methods is to find suitable CVs, which often needs intuition and several trial-and-error optimization steps. Over the years, a plethora of CVs has been developed and applied in the study of crystallization. In this review, we provide a brief overview of CVs that have been developed and used in ES simulations to study crystallization from melt or solution. These CVs can be categorized mainly into four types: (i) spherical particle-based, (ii) molecular template-based, (iii) physical property-based, and (iv) CVs obtained from dimensionality reduction techniques. We present the context-based evolution of CVs, discuss the current challenges, and propose future directions to further develop effective CVs for the study of crystallization of complex systems.

Ion-Mediated Protein Stabilization on Nanoscopic Surfaces.

The emergence of nanoparticles in biomedical applications has made their interactions with proteins inevitable. Nanoparticles conjugated with proteins and peptide-based constructs form an integral part of nanotherapeutics and have recently shown promise in treating a myriad of diseases. The proper functioning of proteins is critical to achieve their biological functions. However, interface issues result in the denaturation of proteins, and the loss of orientation and steric hindrance can adversely affect the function of the conjugate. Furthermore, surface-induced denaturation also triggers protein aggregation, resulting in amyloid-like species. Understanding the mechanistic underpinnings of protein-nanoparticle interactions and controlling their interfacial characteristics are critical and challenging due to the complex nature of the conjugates. In this milieu, we demonstrate that ionic liquids can be suitable candidates for stabilizing protein-nanoparticle interactions by virtue of their excellent protein-preserving properties. We also probe the previously unexplored mechanism of ion-mediated stabilization of the protein molecules on the nanoparticle surface. The protein-nanoparticle conjugates consist of lysozyme and choline-based ionic liquids characterized by optical and electron microscopy techniques combined with surface-sensitive plasmon-enhanced Raman spectroscopy. Furthermore, atomistic molecular dynamics simulations of the conjugates delineate interfacial interactions of the protein molecules and the modulation by the ions, particularly the conformational changes and the dynamic correlation when the protein and specific ionic liquid molecules are adsorbed on the nanoparticle surface. The combined experimental and computational studies showed the synergistic behavior of the ions of the ionic liquids, specifically the orientation and coverage of the anions aided by the cations to control the surface interactions and hence the overall protein stability. These studies pave the way for using ionic liquids, particularly their biocompatible counterparts in nanoparticle-based complexes, as stabilizing agents for biomedical applications.

Cooperative Friedel-Crafts Alkylation of Electron-Deficient Arenes via Catalyst Activation with Hexafluoroisopropanol.

A Friedel-Crafts alkylation of electron-deficient arenes with aldehydes through ''catalyst activation'' is presented. Through hydrogen bonding interactions, the solvent 1,1,1,3,3,3, -hexafluoroisopropanol (HFIP) interacted with the added Brønsted acid catalyst pTSA•H2 O, increasing its acidity. This activated catalyst enabled the Friedel-Crafts alkylation of electron-neutral as well as electron-deficient arenes. Strongly electron withdrawing arenes including arenes with multiple halogen atoms, NO2 , CHO, CO2 R, and CN, groups acted as efficient nucleophiles in this reaction. DFT studies reveal multiple roles of solvent HFIP viz; increasing the Brønsted acidity of the catalyst pTSA•H2 O, and stabilization of the transition states through a concerted pathway enabling the challenging reaction.

Computational investigations on the potential role of hygrophorones as quorum sensing inhibitors against LasR protein of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a gram negative, rod shape bacterium that infects people with compromised immune systems, such as those suffering from AIDS, organ transplantation and cancer. This bacterium is responsible for diseases like cystic fibrosis, chronic lung infection, and ulcerative keratitis. It is diagnosed in most of the patients who were on prolonged ventilation with long term critical care stay. P. aeruginosa develops rapid antimicrobial resistance that is challenging for the treatment and eventually it causes high mortality rate. Thus, the search for potential novel inhibitors that can inhibit the pathogenic activity of P. aeruginosa is of utmost importance. In P. aeruginosa, an important protein, LasR that participates in the gene regulations and expressions has been proposed to be a suitable drug target. Here, we identify a set of hygrophorone molecules as effective inhibitors for this LasR protein based on molecular docking and simulations studies. At first, large number of hygrophorone series of small molecules were screened against the LasR protein and their binding affinities were assessed based on the docking scores. Top scored molecules were selected for calculating various pharmacophore properties, and finally, their potential in inhibiting the LasR protein was delineated by atomistic molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area-based calculations. Both docking and simulations studies reveal that a subset of hygrophorone molecules have a good binding affinity for LasR protein and form stable LasR-inhibitor complexes. The present study illustrates that the hygrophorones can be effective inhibitors for the LasR protein and will spur further in vitro studies that would aid to the ongoing search for new antibiotics.Communicated by Ramaswamy H. Sarma.

Understanding cyclic(alkyl)(amino)carbene-copper complex catalysed N-H and O-H bond addition to electron deficient olefins.

The hydroamination of electron-deficient olefins was carried out using the (CAAC)Cu-Cl (CAAC = cyclic (alkyl)(amino)carbene) catalyst with an excellent yield at room temperature and under an open atmosphere. Furthermore, the catalyst shows excellent efficiency in the hydroaryloxylation and hydroalkoxylation of alkenes under mild conditions. The efficiency of the catalyst was tested for a wide range of substrates with different electronic and steric functionalities. Detailed computational studies have been carried out to understand the mechanism of these Cu(I) catalyzed reactions, which revealed that the reaction proceeds via either a four-membered or a six-membered cyclic transition state containing the copper ion.