Cooperative or Anticooperative: How Noncovalent Interactions Influence Each Other

This computational study examines the key factors that control the structures and energetics of the coexistence of multiple noncovalent interactions. 4-Amino-2-iodophenol is taken as a model that exhibits nine different kinds of noncovalent interactions, viz., cation−π (CP), hydrogen bond (HB) through O (OHB), HB through N (NHB), halogen bond (XB), π–π (PP), metal ion–lone pair (ML) through O (OML), ML through N (NML), charge assisted hydrogen bond (CHB) through O (OCHB), and CHB through N (NCHB). Through all possible combinations of these noncovalent interactions, based on energy, geometry, charge, and atoms in molecules (AIM) analysis, we have systematically analyzed the cooperativity among 40 ternary systems and 105 quaternary systems. We have observed that CP–HB, CP–XB, CP–PP, HB–HB, HB–XB, HB–PP, HB–ML, HB–CHB, XB–PP, XB–ML, XB–CHB, PP–ML, and PP–OCHB can form cooperative ternary systems. While studying the quaternary systems, we have observed that HB, XB, and PP work together by enhancing each other’s strength. The study highlights that the positively charged species enhances HB–HB and HB–PP interactions and forms cooperative HB–HB–CHB, HB–HB–ML, HB–PP–ML, and HB–PP–CHB systems. Surprisingly, OHB–OML–NML, OHB–OML–OCHB, OHB–OML–NCHB, OHB–NML–OCHB, NHB–OML–NML, NHB–OML–NCHB, and NHB–NML–OCHB are also cooperative in nature despite the electrostatic repulsion between two positive charge species. The current study shows the widespread presence of cooperativity as well as anticooperativity in supramolecular assembles

“One-into-Many” Model: An Approach on DFT Based Reactivity Descriptor to Predict the Regioselectivity of Large Systems

“One-into-Many” Model:  An Approach on DFT Based Reactivity Descriptor to Predict the Regioselectivity of Large System

Microscopic Origin of the Solid Electrolyte Interphase Formation in Fire-Extinguishing Electrolyte: Formation of Pure Inorganic Layer in High Salt Concentration

A highly salt-concentrated (HC) electrolyte based on the nonflammable solvent trimethyl-phosphate (TMP) has recently shown an attractive self-extinguishing property in addition to an excellent charge–discharge performance. However, the microscopic understanding of its solid electrolyte interphase (SEI) layer remains an open question. In this Letter, the red moon (RM) method was used to investigate the molecular mechanism of SEI layer formation depending on lithium bis­(fluorosulfonyl)­amide (LiFSA) salt concentration in a TMP-based electrolyte and was able to reproduce successfully the experimental observations, i.e., the “bottom-up” formation mechanism with a thinner and denser SEI layer mainly based on salt reduction in the HC electrolyte. The results showed that a pure dense inorganic layer is formed in the HC electrolyte, which should considerably improve the SEI layer stability leading to a longer lifetime in charge–discharge performance. This new microscopic finding should provide an important guide in designing an effective nonflammable electrolyte to develop advanced, safe secondary batteries

Systemic Codelivery of a Homoserine Derived Ceramide Analogue and Curcumin to Tumor Vasculature Inhibits Mouse Tumor Growth

Prior studies reported significant anticancer activities of ceramides. However, anticancer activities of homoserine based ceramides have not been tested. With a view to compare the anticancer activity of ceramides and homoceramides, in the present study, we have synthesized four serine based and four homoserine based C8-ceramide analogues. Since many cancer cells have shown resistance to ceramides, curcumin is now being used in combination with ceramides because of its ability to reverse multidrug resistance. Aimed at targeting curcumin–ceramide combination to tumor endothelial cells, herein we have used a tumor vasculature targeting liposomes of a newly synthesized pegylated RGDGWK-lipopeptide. Importantly, the liposomal formulations of the homoserine based C8-ceramide analogue containing oleyl chain showed more promising antineoplastic activities under both <i>in vitro</i> and systemic settings than the liposomal formulations of commercially available C8-ceramide. Findings in the mouse tumor growth inhibition study revealed synergistic therapeutic benefit from simultaneous delivery of curcumin and a homoserine based ceramide containing oleyl chain to tumor vasculature. Results in RT-PCR and Western blot experiments suggest that inhibition of solid tumor growth is mediated via inhibition of PI3K-Akt signaling pathway. The present structure–activity study is the first report to demonstrate therapeutic promise of curcumin–homoserine based ceramide combination in antiangiogenic cancer therapy

Efficient Electrocatalytic Hydrogen Evolution from MoS₂‑Functionalized Mo₂N Nanostructures

Molybdenum-based compounds and their composites were investigated as an alternative to Pt for hydrogen evolution reactions. The presence of interfaces and junctions between Mo₂N and MoS₂ grains in the composites were investigated to understand their role in electrochemical processes. Here we found that the electrocatalytic activity of Mo₂N nanostructures was enhanced remarkably by conjugation with few-layer MoS₂ sheets. The electrocatalytic performance of Mo₂N–MoS₂ composites in the hydrogen evolution reaction (HER) was revealed from the high catalytic current density of ∼175 mA cm^–2 (at 400 mV) and good electrochemical stability (more than 18 h) in acidic media. Increasing the amount of MoS₂ in the composite, decreases the HER activity. The mechanism and kinetics of the HER process on the Mo₂N–MoS₂ surface were analyzed using Tafel slopes and charge transfer resistance

Nitric Oxide Dioxygenase Activity of a Nitrosyl Complex of Cobalt(II) Porphyrinate in the Presence of Hydrogen Peroxide via Putative Peroxynitrite Intermediate

The reaction of a cobalt porphyrin complex, [(F8TPP)­Co], 1 {F8TPP = 5,10,15,20-tetrakis(2,6-difluorophenyl)­porphyrinate dianion} in dichloromethane with nitric oxide (NO) led to the nitrosyl complex, [(F8TPP)­Co­(NO)], 2. Spectroscopic studies and structural characterization revealed it as a bent nitrosyl of {CoNO}8 description. It was stable in the presence of dioxygen. However, it reacts with H2O2 in acetonitrile (or THF) solution at −40 °C (or −80 °C) to result in the corresponding Co­(III)-nitrate complex, [(F8TPP)­Co­(NO3)], 3. The reaction presumably proceeds via the formation of a Co-peroxynitrite intermediate. X-Band electron paramagnetic resonance and electrospray ionization–mass spectroscopic studies suggest the intermediate formation of the [(porphyrin)­Co­(III)–O•] radical, which in turn supports the generation of the corresponding Co­(IV)-oxo species during the reaction. This is in accord with the homolytic cleavage of the O–O bond in heme-peroxynitrite proposed in the nitric oxide dioxygenases activity. In addition, the characteristic peroxynitrite-induced phenol ring reaction was also observed

<i>In silico</i> Evaluation of Savirin Derivatives As Inhibitors of the <i>agr</i> Quorum Sensing System of <i>Staphylococcus aureus</i>

Bacterial resistance to current antibacterial agents is a global challenge. The problem of bacterial resistance can be addressed by targeting the bacterial virulence gene expression, particularly quorum sensing (QS) mechanism which is cell to cell communication. Expression of various virulence genes is regulated by the agr QS system of S. aureus, which can be attenuated by inhibiting AgrA-DNA interactions. In this paper molecular docking study was done for savirin and its thirty derivatives with AgrA protein (PDB ID: 4G4K) of S. aureus in order to find out potential inhibitors of AgrA DNA binding activity. Out of the thirty derivatives of savirin, compounds 4, 7, 17, 20, 26 and 30 showed excellent binding scores (less than -10 kcal/mol). Molecular dynamics simulations of the above protein-ligand complexes along with savirin suggested that the complexes of compounds 4, 7, 17, 20, 26 and 30 are stable. MM/PB(GB)SA binding energy calculation showed that compounds 20 and 30 have higher binding affinity among the other compounds. Density functional theory based electronic properties of the compounds were also calculated. Compounds 20 and 30 possess very good drug likeness properties and hence, can be used as potential inhibitors against agr QS system of S. aureus.</p

Heuristics for the Optimal Presentation of Bioactive Peptides on Polypeptide Micelles

Bioactive peptides describe a very large group of compounds with diverse functions and wide applications, and their multivalent display by nanoparticles can maximize their activities. However, the lack of a universal nanoparticle platform and design rules for their optimal presentation limits the development and application of peptide ligand-decorated nanoparticles. To address this need, we developed a multivalent nanoparticle platform to study the impact of nanoparticle surface hydrophilicity and charge on peptide targeting and internalization by tumor cells. This system consists of micelles of a recombinant elastin-like polypeptide diblock copolymer (ELPBC) that present genetically encoded peptides at the micelle surface without perturbing the size, shape, stability, or peptide valency of the micelle, regardless of the peptide type. We created the largest extant set of 98 combinations of 15 tumor-homing peptides that are presented on the corona of this ELPBC micelle via 8 different peptide linkers that vary in their length and charge and also created control micelles that present the linker only. Analysis of the structure–function relationship of tumor cell targeting by this set of peptide-decorated nanoparticles enabled us to derive heuristics to optimize the delivery of peptides based on their physicochemical properties and to identify a peptide that is likely to be a widely useful ligand for targeting across nanoparticle types. This study shows that ELPBC micelles are a robust and convenient system for the presentation of diverse peptides and provides useful insights into the appropriate presentation of structurally diverse peptide ligands on nanoparticles based on their physicochemical properties

Heuristics for the Optimal Presentation of Bioactive Peptides on Polypeptide Micelles

Bioactive peptides describe a very large group of compounds with diverse functions and wide applications, and their multivalent display by nanoparticles can maximize their activities. However, the lack of a universal nanoparticle platform and design rules for their optimal presentation limits the development and application of peptide ligand-decorated nanoparticles. To address this need, we developed a multivalent nanoparticle platform to study the impact of nanoparticle surface hydrophilicity and charge on peptide targeting and internalization by tumor cells. This system consists of micelles of a recombinant elastin-like polypeptide diblock copolymer (ELPBC) that present genetically encoded peptides at the micelle surface without perturbing the size, shape, stability, or peptide valency of the micelle, regardless of the peptide type. We created the largest extant set of 98 combinations of 15 tumor-homing peptides that are presented on the corona of this ELPBC micelle via 8 different peptide linkers that vary in their length and charge and also created control micelles that present the linker only. Analysis of the structure–function relationship of tumor cell targeting by this set of peptide-decorated nanoparticles enabled us to derive heuristics to optimize the delivery of peptides based on their physicochemical properties and to identify a peptide that is likely to be a widely useful ligand for targeting across nanoparticle types. This study shows that ELPBC micelles are a robust and convenient system for the presentation of diverse peptides and provides useful insights into the appropriate presentation of structurally diverse peptide ligands on nanoparticles based on their physicochemical properties

Probing the Most Stable Isomer of Zirconium Bis(phenoxy-imine) Cation: A Computational Investigation

The possibility of coexistence of multiple isomers for zirconium bis­(phenoxy-imine) catalyst has been systematically studied by computational approaches. The energetics among the five different isomers of neutral Zr-catalyst have been assessed quantum mechanically. The results suggest that isomer <i>cis</i>-N/<i>trans</i>-O/<i>cis</i>-Me is the most stable among the five isomers in accordance with the general observations of these kinds of phenoxy-imine catalyst. However, for the polymerization reaction, the active species is known to be the cationic form of the Zr-catalyst. The Zr-cation can exist in three different isomers, viz., <i>cis</i>-N/<i>trans</i>-O (<b>A</b>), <i>cis</i>-N/<i>cis</i>-O (<b>B</b>), and <i>trans</i>-N/<i>cis</i>-O (<b>C</b>), and the presence of flexible ligands makes the modeling considerably challenging to determine the most preferable isomers. For the efficient modeling, altogether 80 different structures for each of the three cationic isomers have been generated by using molecular dynamics simulations, and subsequently, the quantum mechanical optimization of these structures has been performed to obtain the most preferable conformation for each isomer. The existing probability derived from the obtained free energy values suggests that isomer <b>C</b> is comparable with isomer <b>A</b>. Even more, isomer <b>A</b> of the cation can be present in two different conformations, where the orientation of side groups is altered at the imine nitrogen atoms. The transition state calculations also confirm that the Zr-cation can exist as a mixture of three structures, “up–down” and “down–down” orientations of the isomers <b>A</b> along with isomer <b>C’</b>s “up–up” orientation. However, by varying the substituents at imine nitrogen atoms, one could modulate multimodal to unimodal polymerization behavior of the Zr-catalysts. We believe that this study should provide a starting point for theoretically exploring the mechanistic pathway of the complicated polymerization reactions