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Background:  Deep circumflex iliac artery (DCIA)-vascularized iliac graft transposition is a method for treating femoral head osteonecrosis but with inconsistent efficacy. We aim to improve the method of this surgery by recommending the optimal location of the iliac pedicle to satisfy the vascular length for transposition and the blood supply of the vascularized iliac graft., Methods:  The DCIA and its surrounding tissues were assessed on computed tomography angiography images for 100 sides (left and right) of 50 patients. The length of the vascular pedicle required for transposition and the length of the pedicle at different iliac spine positions were compared. The diameter and cross-sectional area of the DCIA and the distance between the DCIA and iliac spine were measured at different points to assess blood supply. We also compared differences in sex and left-right position., Results:  The diameter and cross-sectional area of the DCIA gradually decreased after crossing the anterior superior iliac spine (ASIS), and it approached the iliac bone. However, when the DCIA was 4 cm behind the ASIS (54 sides, 54%), it coursed posteriorly and superiorly away from the iliac spine. The vascular length of the pedicle was insufficient to transpose the vascularized iliac graft to the desired position when it was within 1 cm of the ASIS. The vascular length requirement was satisfied, and the blood supply was sufficient when the pedicle was positioned at 2 or 3 cm., Conclusion:  To obtain a satisfactory pedicle length and sufficient blood supply, the DCIA pedicle of the vascularized iliac graft should be placed 2 to 3 cm behind the ASIS. The dissection of DCIA has slight differences in sex and left-right position due to anatomical differences., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

For decades, studying the dynamic performances of artificial neural networks (ANNs) is widely considered to be a good way to gain a deeper insight into actual neural networks. However, most models of ANNs are focused on a finite number of neurons and a single topology. These studies are inconsistent with actual neural networks composed of thousands of neurons and sophisticated topologies. There is still a discrepancy between theory and practice. In this article, not only a novel construction of a class of delayed neural networks with radial-ring configuration and bidirectional coupling is proposed, but also an effective analytical approach to dynamic performances of large-scale neural networks with a cluster of topologies is developed. First, Coates' flow diagram is applied to acquire the characteristic equation of the system, which contains multiple exponential terms. Second, by means of the idea of the holistic element, the sum of the neuron synapse transmission delays is regarded as the bifurcation argument to investigate the stability of the zero equilibrium point and the beingness of Hopf bifurcation. Finally, multiple sets of computerized simulations are utilized to confirm the conclusions. The simulation results expound that the increase in transmission delay may cause a leading impact on the generation of Hopf bifurcation. Meanwhile, the number and the self-feedback coefficient of neurons are also playing significant roles in the appearance of periodic oscillations.

In recent years, the analysis of the dynamics of annular neural networks has received extensive attention and achieved some achievements. However, most of the current research merely focuses on the single-ring, low-dimension, two rings sharing one neuron cases, without considering the rich coupling modes between rings. In this article, a large-scale time-delay fractional-order dual-loop neural network model with cross-coupling structure is established, in which two rings complete information interaction through two shared neurons. Moreover, the Caputo fractional derivative is introduced in this article to describe the neural network more accurately. First, the transmission time delay between each neuron is selected as the key parameter leading to the bifurcation, and the characteristic equation of the network is creatively derived using the Coates flow graph method. Subsequently, through the holistic element method and magnitude angle formula, we simplify the analytical process. Then, we obtain the stability and Hopf bifurcation criterion of the network. Finally, the conclusions of the theoretical analysis are verified by a series of numerical simulations. The results show that the stability region of the network is closely related to the fractional order, the number of neurons, the distribution of neurons, and the self-feedback coefficients. Moreover, the time delays have a significant effect on the amplitude and period of the Hopf bifurcation.

In comparison to conventional EDM, micro EDM distinguishes itself through its brief discharge duration, narrow discharge channel radius, and concentrated energy density. However, there remains a paucity of comprehensive research on the surface formation characteristics in this domain. This paper delves into the formation mechanism of the recast layer in micro EDM workpieces, scrutinizing the primary factors that influence the formation process and the morphological attributes of the recast layer. We conducted a series of single-pulse experiments and micro EDM trials. Utilizing surface fitting tools, our experimental findings facilitated the derivation of a relational expression between the recast layer thickness of high-speed steel and the discharge parameters in micro EDM. Notably, when the energy is below 100 μJ, the recast layer thickness remains under 10 μm. Specifically, at an energy level of 16 μJ, opting for a smaller capacitance of 2200 pf and a higher voltage of 120 V in micro EDM results in a thinner recast layer. This study serves as a cornerstone for future efforts aimed at controlling and assessing the surface morphology of micro EDM.

The spatiotemporal pattern formation and transition driven by cross-diffusion of the Gray-Scott model are investigated for the early warning of tipping in this paper. The mathematical analyses of the corresponding non-spatial model and spatial model are performed first, which enable us to have a comprehensive understanding. Then, the linear stability analysis and the multiple scale analysis method exhibit that cross-diffusion is the key mechanism for the evolution of spatiotemporal patterns. Through selecting a cross-diffusion coefficient as the bifurcation parameter, the amplitude equations that can describe structural transition and determine the stability of different types of Turing patterns are derived. Ultimately, numerical simulations verify the validity of the theoretical results. It is demonstrated that in the absence of cross-diffusion, the spatiotemporal distribution of substances is homogeneous. Nevertheless, when the cross-diffusion coefficient exceeds its threshold value, the spatiotemporal distribution of substances will become inhomogeneous in space. As the cross-diffusion coefficient increases, the Turing instability region will be extended, leading to various types of Turing patterns: spots, stripes, and a mixture of spots and stripes., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Nano-crystalline diamond has been extensively researched and applied in the fields of tribology, optics, quantum information and biomedicine. In virtue of its hardness, the highest in natural materials, diamond outperforms the other materials in terms of wear resistance. Compared to traditional single-crystalline and poly-crystalline diamonds, nano-crystalline diamond consists of disordered grains and thus possesses good toughness and self-sharpening. These merits render nano-crystalline diamonds to have great potential in tribology. Moreover, the re-nucleation of nano-crystalline diamond during preparation is beneficial to decreasing surface roughness due to its ultrafine grain size. Nano-crystalline diamond coatings can have a friction coefficient as low as single-crystal diamonds. This article briefly introduces the approaches to preparing nano-crystalline diamond materials and summarizes their applications in the field of tribology. Firstly, nano-crystalline diamond powders can be used as additives in both oil- and water-based lubricants to significantly enhance their anti-wear property. Nano-crystalline diamond coatings can also act as self-lubricating films when they are deposited on different substrates, exhibiting excellent performance in friction reduction and wear resistance. In addition, the research works related to the tribological applications of nano-crystalline diamond composites have also been reviewed in this paper.

Diamond films prepared by chemical vapor deposition will exhibit different surface morphologies, which are determined by the texture and the structural perfection of the deposited diamond. In general, its surface morphology can be controlled by adjusting the deposition conditions. In the present work, <110> textured diamond film was deposited on single crystalline silicon through pre-seeding by diamond nanosheets, rather than controlling the deposition conditions. The employed diamond nano-sheets were prepared by cleavage along a plane, exhibiting good crystallinity. Before chemical vapor deposition, the as-prepared diamond nano-sheets were pre-seeded on the surface of single crystalline silicon as nucleation sites for diamond growth. SEM and XRD results show that the prepared diamond films have a <110> texture. FIB observation reveals that diamonds homogeneously grow on the pre-seeded diamond nano-sheets during chemical vapor deposition, achieving the diamond film with <110> texture. Our work provides a new strategy to prepare <110> textured diamond film.

The development of high-contrast stimulus-responsive materials with excited triplet emission is of great significance for anti-counterfeiting, sensor and memory applications, but remains a challenge. Here, we report a strategy for the rational design of stimulus-responsive phenothiazine derivatives with triplet-related dual emissions and high-contrast mechanochromism guided by Polymorph Prediction. The designed phenothiazine derivatives have the characters of simple structures, a facile synthetic procedure, and a good crystalline nature. We found that the crystals of those derivatives with the potential to form both quasi-axial (ax) and quasi-equatorial (eq) conformations could undergo conformation transition and show significant emission difference (Δλ em >100 nm) under mechanical force. Meanwhile, all these phenothiazine derivatives exhibit aggregation-induced emission and emit room-temperature phosphorescence or thermally activated delayed fluorescence. The significant luminescent change of these materials under different stimuli gives them promise for applications in encryption and anti-counterfeiting., (© 2022 Wiley-VCH GmbH.)

Specific 2Ch-2N square interactions between pairs of heterocyclic rings have been the target of many recent crystallographic and computational studies. According to our search of the Cambridge Structural Database (CSD), a number of crystal structures of the derivatives of 1,2,3,5-dichalcogenadiazolyl (DChDA) radicals, which consist of 2Ch-2N square motifs in the dimer units, were extracted. On the basis of the CSD survey results, a set of dimeric complexes of DChDA-based radicals with diverse aryl substituents at the 4-position were selected to model such squares. Similar to that in conventional chalcogen bonds, 2Ch-2N square interactions become stronger as the atomic size of chalcogens increases. Both the orbital term and electrostatics contribute significantly to the attraction of these interactions, while the dispersion contribution is small but unneglectable. Some five-membered aryl substituents, such as imidazole, thiazole, and oxazole, produce markedly enhanced square interactions, leading to a pronounced influence on the distribution of spin populations on DChDA rings.

Protic ionic liquids (PILs) have currently been indicated as promising alternative electrolytes in electrical storage devices, such as lithium-ion batteries and supercapacitors. However, compared with the well-studied aprotic ionic liquids (AILs), the knowledge of the interface between PILs and electrode material surfaces is very rare to date. In this work, the adsorption behaviors of three groups of PILs, i.e. pyrrolidinium-based, imidazolium-based, and ammonium-based, on graphite was systematically investigated using first-principles calculations. The corresponding AILs were also taken into account for comparison. The adsorption mechanism of these ILs on the surface is controlled by the interplay of strong electrostatic interactions between adsorbed ions, weak vdW forces between ILs and substrate, and many aromatic interactions including π-π stacking and C-H/N-Hπ contacts. PILs do show quite different preferential interfacial interactions and structures on the graphite surface with respect to AILs, arising mainly from the anion-substrate interactions. Particularly, proton transfer takes place in the PILs consisting of the imidazolium/ammonium cation and the nitrate anion in the gas phase, but it tends to be attenuated or even disappears on graphite caused by interfacial interactions.

Noncovalent chalcogen-chalcogen interactions are being actively investigated from both crystallographic and theoretical viewpoints in recent years. According to our search of the Cambridge Structural Database (CSD), a huge number of crystal structures containing triangular Ch 3 synthons were extracted. On the basis of the results of the CSD survey, a series of trimeric complexes of organic divalent chalcogen molecules were selected to model such interaction motifs. Similar to that in conventional chalcogen bonds, triangular interchalcogen interactions become gradually stronger along the sequence of Ch = S, Se, Te. Particularly, hydrogen bonds between the chalcogen centers and the H atoms in the substituents occur, which play a significant role in stabilizing the Ch 3 motifs in the trimers. Through multibody energy calculations, the complexes under study exhibit no or only weak cooperativity. Finally, the differences between the Ch 3 interaction motifs and the well-studied windmill X 3 bonding (X means halogen and this is halogen bond) patterns were elucidated.

Energy-structure-function (ESF) maps can aid the targeted discovery of porous molecular crystals by predicting the stable crystalline arrangements along with their functions of interest. Here, we compute ESF maps for a series of rigid molecules that comprise either a triptycene or a spiro-biphenyl core, functionalized with six different hydrogen-bonding moieties. We show that the positioning of the hydrogen-bonding sites, as well as their number, has a profound influence on the shape of the resulting ESF maps, revealing promising structure-function spaces for future experiments. We also demonstrate a simple and general approach to representing and inspecting the high-dimensional data of an ESF map, enabling an efficient navigation of the ESF data to identify 'landmark' structures that are energetically favourable or functionally interesting. This is a step toward the automated analysis of ESF maps, an important goal for closed-loop, autonomous searches for molecular crystals with useful functions.

Background: Wang successfully replanted the severed fingers of 2 patients after cryopreservation in 2002 and 2003, which has enabled us to share our own experience for the knowledge interests of our colleagues and to further develop this technology., Methods: Fifteen healthy adult male Sprague-Dawley rats were selected and divided into 5 groups (group 1: normal control, group 2: cryopreservation with protectant, group 3: cryopreservation without protectant, group 4: 6-hour postoperative, and group 5: 72-hour postoperative). After harvesting the hind limbs, cryoprotectant was applied to 20 limbs, and the rest were cryopreserved without cryoprotectant for 15 days. After being thawed, the amputated limb was replanted in situ. Nerves, skins and gastrocnemius muscles were collected for hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and transmission electron microscopy observation., Results: Muscle and skin tissues treated with cryoprotectant restored a better outline after being frozen than those not treated, whereas nerves were not significantly different between the 2 groups. After replantation, some of the myofibrils of the muscle were in disarray, but the sarcomere structure remained intact at approximately 6 hours postoperatively. At 72 hours, a transmission electron microscopy scan showed that the myofibrillar arrangement was disorderly, with segmental myofilament breakage, and the sarcomere structure was destroyed in some cases. In addition, the scan revealed increased apoptotic cells and collapse of basic structures in the skin and nerves., Conclusions: Relative to that of skin and neuronal tissue, the replantation of muscle tissues through the cryopreservation method is more difficult.

Osteosarcoma is the most common bone sarcoma in adolescents. Decorin (DCN) has been proposed to be a new anti-osteosarcoma therapeutic strategy. Our previous study has loaded decorin on titanium (Ti) surface by polydopamine (DOPA) as an anchor to enhance osseointegration. In this study, we investigated the effect of decorin-coated Ti substrates (TI-DOPA-DCN) on the oncogenic potential of osteosarcoma cells SAOS-2. The substrates were placed in 24-well plates for cell culture. Cell viability was determined by Cell Counting Kit-8 (CCK8) assay. Apoptosis was evaluated by DAPI staining and Annexin V-FITC/PI double staining analysis. Cell cycle was analyzed by flow cytometry. Cell migration and invasion were evaluated by Transwell assay. For co-culture, the pre-osteogenic cells MEC3T3-E1 and osteosarcoma cells SAOS-2 were stained with cell membrane fluorescent dyes, and then mixed (1:1) for co-culture. The cells were observed under a fluorescence microscope at four time points of 24, 48, 72, and 96 h. The results showed that TI-DOPA-DCN substrate can selectively inhibit cell proliferation of osteosarcoma cells but not pre-osteoblasts. However, the cell cycle of SAOS-2 was not affected by TI-DOPA-DCN substrates. Both DAPI staining and Annexin V-FITC/PI double staining analysis revealed that TI-DOPA-DCN substrates induced apoptosis of osteosarcoma cells. Transwell assay showed that TI-DOPA-DCN substrates inhibited invasion and migration of osteosarcoma cells. Moreover, TI-DOPA-DCN substrates inhibited the growth of osteosarcoma cells but promoted that of pre-osteoblasts in the coculture system. Taken together, these findings suggested that decorin coating on Ti surface simultaneously inhibited the oncogenic potential of osteosarcoma cells but enhanced cell growth of pre-osteoblasts, which could be applied to surface modification of Ti orthopedic implant., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Although halogen bond (XB), a typical σ-hole noncovalent interaction, has been widely exploited in organocatalysis within the last two decades, only very recently has its sister σ-hole interactions, such as chalcogen bond (ChB) and pnictogen bond (PnB), begun to be explored for potential applications in catalysis. Herein, a detailed comparison investigation of PnB, ChB, and XB interactions in catalytic systems was performed from a theoretical point of view. Owing to the excellent properties of the pentafluorophenyl moiety (C 6 F 5 ) in catalysis, the complexes of (C 6 F 5 ) 3 Pn, (C 6 F 5 ) 2 Ch, and C 6 F 5 X with chloride ion were firstly studied. Then, we successively substituted C 6 F 5 by phenyl groups, to examine the influence of substituents on the characteristics of such interactions. In addition, several halogen-bonded complexes between the donor 1,3,5-trifluoro-2,4,6-triiodobenzene (C 6 F 3 I 3 ) and heavier Pn and Ch species as acceptors were also investigated. Our calculations showed that the interactions become gradually stronger upon going from row 3 to 5 and from main group VII to V, which correlates well with the experimental observations. As the strength of the interactions enhances, the contribution of electrostatics to the attraction increases, while the orbital term contribution becomes smaller. Particularly, the significant differences between the three types of σ-hole interactions found in catalysis and anion transport were clarified.

Background: Cyamella,the sesamoid bones of the popliteus muscle, are rare in humans. Snapping knee is an uncommon problem which can be difficult to diagnose., Case Presentation: In this case, we report a 24-year-old male with snapping knee caused by symptomatic cyamella in the popliteus tendon. A large cyamella was identified upon surgery and was removed. Postoperatively, the patient had immediate relief of preoperative symptoms, and there were no signs of recurrence after 1 years of follow-up., Conclusions: Although not previously suggested, symptomatic cyamella in the popliteus tendon should be considered as part of the differential diagnosis of the snapping knee.

In recent years, chalcogen bonding (ChB), a typical σ-hole interaction, has shown great potential as a bottom-up design approach for specific applications. According to our survey of the Cambridge Structural Database (CSD), a large number of crystal structures containing 2Ch-2N square and hexagon interaction motifs were extracted. On the basis of the CSD search results, the 2Ch-2N square interactions in the dimers of 2,1,3-benzochalcogenadiazole 1 and 2,1,3-pyridochalcogenadiazole 2, together with 2Ch-2N hexagon interactions in the dimers of chalcogenazolo-pyridine 3 and triazolo-chalcogenadiazole 4, were firstly studied. Then, substituent effects on these peculiar interactions were thoroughly examined by introducing a diversity of small, non-aromatic substituents at the 4,7-positions of the 1S scaffold and various aryl substituents at the 2-position of the 3Te scaffold. Our calculations showed that the major contribution to the attraction of such bidentate ChB interactions is electrostatics, while the orbital term also plays an important role. Some strong electron-withdrawing substituents, such as NO 2 , CN, and CF 3 , tend to enhance square ChB interactions, while C 6 F 5 and CF 3 substituents with a strong electron-withdrawing ability strengthen hexagon ChB interactions. Particularly, a good linear correlation has been established between the binding energies of the dimers under study and both the surface electrostatic potential (ESP) maxima for the Ch σ-holes and the minimum surface ESP of the N atoms, which provides reasonable models to evaluate these interactions. The results reported in this work will provide design guidance for the applications of 2Ch-2N cyclic motifs in materials science and biochemistry.

Efficient approaches with high precision are essential for understanding the formation and stability of noncovalent interaction complexes. Here, 21 noncovalent interaction complexes involving π-system are selected and grouped in three subsets according to ETS-NOCV method: dispersion-dominated, electrostatic-dominated, and mixed. We mainly focus on examining the performance of random-phase approximation (RPA) on these π systems. The tested RPA-based method includes standard RPA and its variants including the related single excitations (SEs), renormalized single excitations (rSEs), second-order screened exchange (SOSEX), and the renormalized second-order perturbation theory (rPT2). The routine second-order Møller-Plesset perturbation theory (MP2) and three popular DFT-D functionals (M06-2X-D3, ωB97XD, and PBE-D3(BJ)) are also assessed for comparison. In this work, besides the calculation of interaction energies at Dunning-type aug-cc-pVDZ and aug-cc-pVTZ basis set, we also present a larger database of interaction energies calculated using MP2 and RPA methods with Dunning-type aug-cc-pVQZ basis set. An accurate CCSD(T)/CBS scheme is used to provide benchmark database. In addition to the high-level results, we also provide potential energy surfaces (PES) of different interaction type. Among all the tested methods, MP2 has a satisfactory performance on electrostatic-dominated and mixed-type systems, except for dispersion-dominated systems. DFT-D functionals, especially ωB97XD functional, has a balanced performance across all the tested systems. Importantly, for RPA-based methods, the calculation accuracy can be dramatically improved by taking into account SE or exchange effects, especially in the mixed complexes. We conclude that rPT2 among all the test RPA-based methods gives an overall satisfactory performance across different interaction types. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

Significant research efforts, mostly experimental, have been devoted to finding high-performance anode materials for lithium-ion and potassium-ion batteries; both graphitic carbon-based and carbon nanotube-based materials have been generating huge interest. Here, first-principles calculations are performed to investigate the possible effects of doping defects and the varying tube diameter of carbon nanotubes (CNTs) on their potential for battery applications. Both adsorption and migration of Li and K are studied for a range of pristine and nitrogen-doped CNTs, which are further compared with 2D graphene-based counterparts. We use detailed electronic structure analyses to reveal that different doping defects are advantageous for carbon nanotube-based and graphene-based models, as well as that curved CNT walls help facilitate the penetration of potassium through the doping defect while showing a negative effect on that of lithium., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Joint contracture is a common complication for people with joint immobility that involves fibrosis structural alteration in the joint capsule. Considering that endoplasmic reticulum (ER) stress plays a prominent role in the promotion of tissue fibrosis, we investigated whether the unfolded protein response (UPR) contributes to the fibrotic development in immobilization-induced knee joint contractures. Using a non-traumatic rat knee joint contracture model, twelve female Sprague-Dawley rats received knee joint immobilization for a period of 8 weeks. We found that fibrosis protein markers (type I collagen, α-SMA) and UPR (GRP78, ATF6α, XBP1s) markers were parallelly upregulated in rat primary cultured synovial myofibroblasts. In the same cell types, pre-treatment with an ER stress inhibitor, 4-phenylbutyric acid (4-PBA), not only abrogated cytokine TGFβ1 stimulation but also reduced the protein level of UPR. Additionally, high reactive oxygen species (ROS) generation was detected in synovial myofibroblasts through flow cytometry, as expected. Notably, TGFβ1-induced UPR was significantly reduced through the inhibition of ROS with antioxidants. These data suggest that ER stress act as a pro-fibrotic stimulus through the overexpression of ROS in synovial fibroblasts. Interestingly, immunohistochemical results showed an increase in the UPR protein levels both in human acquired joint contractures capsule tissue and in animal knee joint contracture tissue. Together, our findings suggest that ER stress contributes to synovial myofibroblastic differentiation in joint capsule fibrosis and may also serve as a potential therapeutic target in joint contractures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In this work, halogen bonding interactions in the complexes of two new nitroxide radicals, which contain both a halogen-bond-donor group and an electron-spin-resonance-active radical unit, were investigated using density functional theory calculations. For comparison, the corresponding hydrogen-bonded complexes were also examined. Halogen bonds in these systems are predicted to be linear and much stronger than hydrogen bonds. To further understand the nature of these interactions, many theoretical methods, such as atoms in molecules, noncovalent interaction index, localized orbital locator, energy decomposition analysis, electron density difference, and electron spin densities, were employed. Compared with hydrogen bonds, halogen bonds have more open shell and covalent interaction components. Particularly, the formation of halogen bonds changes the ratio of different conformations, leading to spin density shift on certain atoms. The results reported herein will assist in the design of new functional probes for the detection of halogen bonding.

Orthopedic implants, using materials such as titanium, are extensively used in clinical surgeries. Despite its popularity, titanium is still inadequate to reliable osseointegration due to aseptic loosing. Fibrous encapsulation on the titanium implant interface prevents osseointegration and leads to the loosing of orthopedic implant. In this study, decorin was loaded on titanium surface by polydopamine film to examine fibrous encapsulation inhibition and bone growth acceleration. The coating of decorin was evaluated by X-ray photoelectron spectroscopy (XPS) and fluorescence microscopy. Quantitative analysis showed increased decorin coating on titanium surface when decorin in the loading solution increases. To test the effect of decorin modification, fibroblast and osteoblast cultures were utilized in vitro. The results showed that the functions of fibroblasts (proliferation, migration and collagen synthesis) were significantly attenuated on the decorin-modified surfaces and this anti-fibrous effect could be due to fibrotic gene suppression by decorin. In contrast, osteoblastic activities, such as calcium deposition and alkaline phosphatase (ALP) activity, were enhanced by the modified decorin. These results suggest that decorin coating on titanium surface inhibited proliferation and function of fibroblasts and improved that of osteoblasts. Therefore, this study is potentially useful for enhancing orthopedic implant., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Triphenylamine-functionalized boron 2-(2'-pyridyl)imidazole complex bearing no alkyl chains or H-bond unit was found to be able to gelate a series of solvents, and the balanced intermolecular π-π interactions play an important role in its supramolecular self-assembly. The gelator molecule is piezochromic, and the dried gel responded to pressure more sensitively than regular crystalline powder., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this work, the interactions between imidazolium-based ionic liquids and some stable radicals based on 2,2,6,6-tetramethylpiperidine-1-yloxyl (TEMPO) have been systematically investigated using density functional theory calculations at the level of M06-2x. Several different substitutions, such as hydrogen bonding formation substituent (OH) and ionic substituents (N(CH3)3(+) and OSO3(-)), are presented at the 4-position of the spin probe, which leads to additional hydrogen bonds or ionic interactions between these substitutions and ionic liquids. The interactions in the systems of the radicals containing ionic substitutions with ionic liquids are predicted much stronger than those in the systems of neutral radicals, resulting in a significant reduction of the mobility of ionic radicals in ionic liquids. To further understand the nature of these interactions, the natural bond order, atoms in molecules, noncovalent interaction index, electron density difference, energy decomposition analysis, and charge decomposition analysis schemes were employed. The additional ionic interactions between ionic radicals and counterions in ionic liquids are dominantly contributed from the electrostatic term, while the orbital interaction plays a major role in other interactions. The results reported herein are important to understand radical processes in ionic liquids and will be very useful in the design of task-specific ionic liquids to make the processes more efficient.

By introducing a flexible component into a molecular building block, we present an unprecedented alkyl-decorated flexible crystalline material with a breathing behavior. Its selective adsorption is derived from the breathing effect induced by a guest triggered alkyl transformation. This feature allows the crystal to take up 2.5 mmol g(-1) of chloroform with high adsorption selectivity (CHCl3 /EA >2000 for example), implying a potential application in sorption separation and chemical sensors., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Joint contracture is a fibroproliferative disorder that restricts joint mobility, resulting in tissue degeneration and deformity. However, the etiology of joint contracture is still unknown. Chaperonin containing T-complex polypeptide subunit eta (CCT-eta) is reported to increase in fibrotic diseases. The purpose of this study was to investigate whether CCT-eta is implicated in joint contracture and to determine the role of CCT-eta in the progression of joint contracture by analyzing a rat model. We immobilized the left knee joint of rat by internal fixation for 8 weeks. The non-immobilized right leg served as a control. The range of motion (ROM) of the knee was investigated. Fibroblasts were obtained from the posterior joint capsule of the joints. The outcome was followed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, fibroblast migration assay, and collagen assay. The effect of CCT-eta on the functions of fibroblasts was observed by utilizing a short inhibitory RNA (siRNA) targeting CCT-eta. The ROM of the immobilized joints was significantly limited compared to the contralateral joints (p < 0.05). Fibroblasts derived from the contractive joints showed higher mRNA and protein expressions of CCT-eta in parallel with alpha-smooth muscle actin (α-SMA) compared to the cells from the contralateral knees (p < 0.05). siRNA-mediated downregulation of CCT-eta inhibited the expressions of both CCT-eta and α-SMA. Moreover, the reduction of CCT-eta also significantly decreased fibroblast functions such as cell mobility and collagen synthesis (all p < 0.05). Our findings indicate that CCT-eta appears to be a potential marker of joint contracture disease.

The M4(CO)12 molecules Co4(CO)12, Rh4(CO)12, and Ir4(CO)12 have two low-lying structures, the all-terminal structure with Td symmetry and the triply bridged structure with C3v symmetry. A total of 45 density functional theory (DFT) methods have been used to predict structures and vibrational frequencies for Co4(CO)12, Rh4(CO)12, and Ir4(CO)12. The different DFT methods show a broad range of energy differences ΔE = E(Td) - E(C3v). For Rh4(CO)12, none of the 45 DFT predictions is within 11 kcal/mol of the 2005 experimental value of 5.1 ± 0.6 kcal/mol reported by Allian and Garland (Dalton Trans. 2005, 1957 - 1965). For the challenging Ir4(CO)12 molecule, 21 DFT methods predict the correct Td structure, while 24 DFT methods predict the C3v structure to lie lower in energy. This research reveals many peculiar problems in the computation of the vibrational frequencies for the all-terminal structure.

Metal-containing ionic liquids (ILs) have been recognized as potential solvents, catalysts, catalyst precursors and reagents for many organic processes. In this work, several quantum-chemical parameters, including the surface electrostatic potential (Vs,max and Vs,min), the lowest surface average local ionization energy (I̅s,min), and the electrostatic potential at the position of an atom (EPnuc), were adopted to understand the acidity/basicity of metal-containing ILs. Chlorometallate-based ILs show stronger acidity than conventional ILs, because of the increased electron-deficiency of the imidazole ring upon the incorporation of metal chloride. For the ILs with the Ag-coordinated cations, the acidity tends to attenuate while the basicity becomes stronger, as compared to traditional ILs. In addition, the regional Fukui function was also used to assess the molecular distribution of the Lewis acidity/basicity of the ILs under study. Overall, the introduction of metals into either the cations or the anions influences the acidity/basicity of ILs to a large degree, which would be beneficial for their certain applications, such as catalysis and extraction. We hope that the results presented here will assist in the development of novel metal-containing ILs with desirable properties.

The challenge motivating this paper is to induce, by chemical substitution, a silylyne, SiR, or a congeneric carbyne, CR, to adopt the high-spin quartet rather than the low-spin doublet as its ground state. The difficulty is seen in the preference for the doublet of the parent SiH (doublet-quartet energy difference ∼39 kcal/mol, favoring the doublet) or CH (∼17 kcal/mol). Strategies for having high-spin ground state parallel those for silylenes and carbenes: greater electropositivity (σ-donation) and π-acceptance of the single substituent favor the high-spin state. The electronegativity trend can be understood from an ions in molecules way of thinking already present in the literature in the works of Boldyrev and Simons, and of Mavridis and Harrison; i.e., the quartet ground state spin of some CR/SiR species is largely determined by the ground state spin of C(-)/Si(-). In this study, we provide a diabatization analysis that solidly confirms the ions in molecules picture and explains the difference in the equilibrium internuclear distances for the two spin states. In general, electronegativity dominates the ordering of spin states. π-Acceptors also help to lower the quartet state energy of the many carbynes (silylynes) examined, whose range of doublet-quartet differences calculated is impressive, 120 (100) kcal/mol. The qualitative understanding gained leads to the prediction of some quartet-ground state carbynes (CMgH, CAlH2, CZnH, CSiH3, CSiF3, etc.) and a smaller number of silylynes (SiMgH, SiMgF, SiBeH, etc.). A beginning is made on the energetics of approach geometries of the fragments in the highly exoergic dimerization of CH to acetylene; it should proceed for the ground state doublet CH through C2h-like trajectories, with no activation energy.

Pioneering synthetic research by the groups of Grutzmacher and Goicoechea have made possible the preparation of 2-phosphaethynolates (PCO(-)). The obvious question arises: can progress be made toward AsCO(-), SbCO(-), and BiCO(-)? Here the properties of all five anion congeners ECO(-) (E = N, P, As, Sb, Bi) were systematically investigated using ab initio coupled-cluster methods with correlation-consistent basis sets cc-pVXZ (X = D, T, Q). These anions exhibit linear structures with significant natural bond orbital negative charge on both the E and O atoms. These species should react with electrophiles via attack at either center. On going from nitrogen to bismuth, with the atomic radius increasing, the bond between E and C becomes weaker, while the C-O bond tends to be slightly stronger. By the time one gets to BiCO(-), the C-O bond distance is 1.181 Å, indicating a very strong double bond. Relative to the PCO(-) anion, which is reactive toward several unsaturated compounds, the As/Sb/BiCO(-) anions may undergo cycloaddition more readily with unsaturated substrates. The dissociation energy of the E-C bond, except for that of NCO(-), is predicted to be much less than that of the C-O bond. These dissociation energies are 76 kcal/mol (P(-)-CO), 58 kcal/mol (As(-)-CO), 37 kcal/mol (Sb(-)-CO), and 28 kcal/mol (Bi(-)-CO). Even the BiCO(-) anion should be achievable in the laboratory. The vibrational frequencies for these anions are predicted, and our results should assist in the experimental characterization and exploration of the heavier congeners ECO(-).

Transition metal-containing ionic liquids (TM-ILs) have attracted a great deal of attention in recent years, due to their unique physical and chemical properties. In this work, several representative TM-ILs, such as the cations consisting of silver(I) center coordinated by two n-alkylimidazole ligands ([(C(n)(im))Ag(mim)](+)) and the anions involving mercury(II) (HgCl3(-)), zinc(II) (ZnCl3(-)), and rhenium(VII) (ReO4(-)), were investigated using density functional theory calculations. First, the structural and energetic properties of the ion pairs for these TM-ILs have been examined in detail and compared with properties for conventional ILs. It was found that the interactions between the cations and anions, including hydrogen bonds and electrostatic interactions, in TM-ILs become weaker in strength than those in traditional ILs. In particular, the calculated geometric and energetic features compare fairly well with the experimental results, such as melting points and X-ray crystal structures of these TM-ILs. Then, the structures and energetics of ion-pair dimers for three ILs containing HgCl3(-), ZnCl3(-), and ReO4(-) were also explored, to gain a deeper understanding of the properties of TM-ILs. Finally, a survey of the Cambridge Structural Database (CSD) was undertaken to provide some crystallographic implications of TM-ILs.

Halogen bond has attracted a great deal of attention in the past years for hit-to-lead-to-candidate optimization aiming at improving drug-target binding affinity. In general, heavy organohalogens (i.e., organochlorines, organobromines, and organoiodines) are capable of forming halogen bonds while organofluorines are not. In order to explore the possible roles that halogen bonds could play beyond improving binding affinity, we performed a detailed database survey and quantum chemistry calculation with close attention paid to (1) the change of the ratio of heavy organohalogens to organofluorines along the drug discovery and development process and (2) the halogen bonds between organohalogens and nonbiopolymers or nontarget biopolymers. Our database survey revealed that (1) an obviously increasing trend of the ratio of heavy organohalogens to organofluorines was observed along the drug discovery and development process, illustrating that more organofluorines are worn and eliminated than heavy organohalogens during the process, suggesting that heavy halogens with the capability of forming halogen bonds should have priority for lead optimization; and (2) more than 16% of the halogen bonds in PDB are formed between organohalogens and water, and nearly 20% of the halogen bonds are formed with the proteins that are involved in the ADME/T process. Our QM/MM calculations validated the contribution of the halogen bond to the binding between organohalogens and plasma transport proteins. Thus, halogen bonds could play roles not only in improving drug-target binding affinity but also in tuning ADME/T property. Therefore, we suggest that albeit halogenation is a valuable approach for improving ligand bioactivity, more attention should be paid in the future to the application of the halogen bond for ligand ADME/T property optimization.

A new turn-on fluorescent chemosensor, DPPL1, was rationally designed and synthesized based on diketopyrrolopyrrole (DPP), which presented high sensitivity and selectivity for Zn(2+). Specifically, DPPL1 presented a large emission enhancement and a 70 nm blue-shift upon Zn(2+) binding. (1)H NMR titrations, studies into the pH effects and DFT calculations further proved that this phenomenon was due to both photo-induced electron transfer (PET) and intra-molecular charge transfer (ICT) processes. More importantly, DPPL1 was successfully used for imaging Zn(2+) in living HeLa cells. To the best of our knowledge, this is the first DPP-based fluorescent chemosensor to recognize Zn(2+) ions in living cells with a large blue-shift and a fluorescent enhancement based on both photo-induced electron-transfer (PET) and intramolecular charge-transfer (ICT) effects. Meanwhile, we have also provided a new effective platform for the development of fluorescent chemosensors for other analytes.

Database survey in this study revealed that about one-third of the protein structures deposited in the Protein Data Bank (PDB) contain arginine-arginine (Arg-Arg) pairing with a carbon···carbon (CZ···CZ) interaction distance less than 5 Å. All the Arg-Arg pairings were found to bury in a polar environment composed of acidic residues, water molecules, and strong polarizable or negatively charged moieties from binding site or bound ligand. Most of the Arg-Arg pairings are solvent exposed and 68.3% Arg-Arg pairings are stabilized by acidic residues, forming Arg-Arg-Asp/Glu clusters. Density functional theory (DFT) was then employed to study the effect of environment on the pairing structures. It was revealed that Arg-Arg pairings become thermodynamically stable (about -1 kcal/mol) as the dielectric constant increases to 46.8 (DMSO), in good agreement with the results of the PDB survey. DFT calculations also demonstrated that perpendicular Arg-Arg pairing structures are favorable in low dielectric constant environment, while in high dielectric constant environment parallel structures are favorable. Additionally, the acidic residues can stabilize the Arg-Arg pairing structures to a large degree. Energy decomposition analysis of Arg-Arg pairings and Arg-Arg-Asp/Glu clusters showed that both solvation and electrostatic energies contribute significantly to their stability. The results reported herein should be very helpful for understanding Arg-Arg pairing and its application in drug design.

In recent years, several specific imidazolium-based ionic liquids with halogen substituents on the imidazole ring as well as on the alkyl chains have been reported. In this work, noncovalent interactions in four halogenated ionic liquids, i.e. 2-bromo-/iodo- and 4,5-dibromo-/diiodo-1,3-dimethylimidazolium trifluoromethanesulfonates, were systematically investigated using density functional theory calculations. The structural and energetic properties of the ion pairs for such ionic liquids have been fully examined and compared with the non-halogenated ones. It was found that C-X···O halogen bonds, C-H···O hydrogen bonds, and electrostatic interactions with the anion located over the imidazole ring in the ion pairs. In addition, the structures and energetics of two ion pairs for such ionic liquids were also explored to reproduce experimental observations. The halogen-bonded ring structures and the conformers with the concurrent C-H···O and C-X···O contacts were predicted, consistent with the X-ray crystal structures of corresponding organic salts. Finally, the implications of the observed structural and energetic features of ion pairs on the design of halogen-bonding ionic liquids were discussed. The results presented herein should provide useful information in the development of novel halogenated ionic liquids used for specific tasks ranging from organic synthesis to gas absorption.

According to our survey of the Cambridge Structural Database (CSD), a great number of crystal structures, in which halogen bonds and aromatic stacking interactions are present and play an important role in crystal packing, have been extracted. In this work, ab initio calculations at the MP2 level of theory were performed to investigate the mutual influence between halogen bonds and π-π stacking interactions. Different energetic effects are observed in the studied complexes where the two kinds of noncovalent interactions coexist, which can be rationalized by the direction of charge transfer for the two interactions. These effects have been analyzed in detail in terms of the structural, energetic, and charge transfer properties of the complexes. In addition, the quantum theory of atoms in molecules (QTAIM) was also employed to characterize the interactions and to examine the strengthening or weakening of the interactions, depending on the variations of electron density on the bond and cage critical points. Finally, certain crystal structures retrieved from the CSD have been selected to provide experimental evidence of the combination of the two interactions.

The structures and properties of noncovalent interactions involving three imidazoliophane receptors 1-3 and halide anions have been investigated by means of density functional theory calculations. To account for the influence of the solvent environment, the implicit polarized continuum model was also employed. For the halogenated cyclophane receptors 1 and 2, the halide ions are held by a bidentate array of halogen bonds (C-Br/C-I...X(-)), while multiple hydrogen-bonding interactions (C-H...X(-)) are present in the complexes of the nonhalogenated macrocyclic receptor 3. To accommodate the negatively charged guest anions, the structures of 1 and 2 fully reorganize into a calix-like shape, while both the imidazole and benzene rings in 3 tend to point towards the anions and thus rotate to form a cage-like shape. In both the gas phase and aqueous solution, the binding affinities of the anions for halogen-bonding receptors 1 and 2 become stronger than those for hydrogen-bonding receptor 3. The results reported here should prove to be of great value in the design and synthesis of effective and selective anion receptors based on halogen bonding.

The interplay between halogen bonds and cation-π interactions is investigated by ab initio calculations at the MP2 level of theory. Different energetic effects are observed in the studied complexes in which halogen bonds and cation-π interactions coexist, which can be ascribed to the direction of charge transfer for the two interactions. These effects are analyzed in detail in terms of the structural, energetic, and charge-transfer properties of the complexes. In addition, the quantum theory of atoms in molecules is employed to characterize the interactions and to examine their enhancement and attenuation in terms of the variations in electron density at the bond and cage critical points. Finally, experimental evidence for a combination of the two interactions is obtained from the Cambridge Structural Database., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: A large number of drugs and drug candidates in clinical development contain halogen substituents. For a long time, only the steric and lipophilic contributions of halogens were considered when trying to exploit their effects on ligand binding. However, the ability of halogens to form stabilizing interactions, such as halogen bonding, hydrogen bonding and multipolar interactions, in biomolecular systems was revealed recently. Halogen bonding, the non-covalent interaction in which covalently bound halogens interact with Lewis bases, has now been utilized in the context of rational drug design., Areas Covered: The purpose of this review is to show how halogen bonding could be used in drug design, and in particular, to stimulate researchers to apply halogen bonding in lead optimization. This review article covers the recent advances relevant to halogen bonding in drug discovery and biological design over the past decade, including database survey of this interaction in protein-ligand complexes, molecular mechanical investigations of halogen bonding in drug discovery and applications of this interaction in the development of halogenated ligands as inhibitors and drugs for protein kinases, serine protease factor Xa, HIV reverse transcriptase and so on., Expert Opinion: Halogen bonding should intentionally be used as a powerful tool, comparable with hydrogen bonding, to enhance the binding affinity and also influence the binding selectivity. Rational design of new and potent inhibitors against therapeutic targets through halogen bonding continues to be an exciting area, which will be further elucidated with the combination of various experimental techniques and theoretical calculations in the forthcoming years.

Energetic effects between halogen bonds and anion-π or lone pair-π interactions have been investigated by means of ab initio MP2 calculations. 1,4-diiodo-perfluorobenzene, a very effective building block for crystal engineering based on halogen bonding, is selected in this work both as electron-deficient π aromatic ring and as halogen bond donor. Additive and diminutive effects are observed when halogen bonds and anion-π/lone pair-π interactions coexist in the same complex, which can be ascribed to the same direction of charge transfer for the two interactions. These effects have been analyzed in detail by the structural, energetic, and AIM properties of the complexes. Finally, experimental evidence of the combination of the interactions has been obtained from the Cambridge Structural Database.

The CheA histidine kinase, a model of TCS (the two-component system), mediates the signal transduction pathway of bacterial chemotaxis via autophosphorylation. Since the TCSs are rarely found in mammalians, they have become attractive targets for the development of new antibiotics. To characterize the autophosphoryl-transfer mechanism of CheA histidine kinase, molecular dynamics simulations combined with quantum mechanics/molecular mechanics calculations were employed on the constructed 3D model of P1-P4-ATP complex. A two-step reaction mechanism was proposed and confirmed by our computations: the autophosphoryl-transfer reaction takes place followed by a rapid and reversible conformational change from ground state to prechemistry state. In addition, a two-dimensional potential energy surface was calculated for autophosphorylation, and the transition state displays an associative character. Moreover, we found Lys48 serves as the catalytic acid to stabilize transition state through a water-mediated proton-transfer pathway, and Glu67 acts as not only a hydrogen bond acceptor but also a structure anchor to modulate the imidazole ring of His45 in the active site. Our findings clearly provide a detailed autophosphoryl-transfer mechanism of CheA histidine kinase and thus are important for discovering new antibiotics.

For proof-of-concept of halogen bonding in drug design, a series of halogenated compounds were designed based on a lead structure as new inhibitors of phosphodiesterase type 5. Bioassay results revealed a good correlation between the measured bioactivity and the calculated halogen bond energy. Our X-ray crystal structures verified the existence of the predicted halogen bonds, demonstrating that the halogen bond is an applicable tool in drug design and should be routinely considered in lead optimization.

A systematic study of halogen bonding interactions in gas phase and in solution was carried out by means of quantum chemical DFT/B3LYP method. Three solvents with different polarities (chloroform, acetone, and water) were selected, and solvation effects were considered using the polarized continuum model (PCM). For charged halogen-bonded complexes, the strength of the interactions tends to significantly weaken in solution, with a concomitant elongation of intermolecular distances. For neutral systems, halogen bond distances are shown to shorten and the interaction energies change slightly. Computations also reveal that in the gas phase the binding affinities decrease in the order Cl(-) > Br(-) > I(-), while in solution the energy gaps of binding appear limited for the three halide anions. According to free energy results, many systems under investigation are stable in solution. Particularly, calculated free energies of formation of the complexes correlate well with halogen-bonding association constants determined experimentally. The differences of the effects of solvent upon halogen and hydrogen bonding were also elucidated. This study can establish fundamental characteristics of halogen bonding in media, which would be very helpful for applying this noncovalent interaction in medicinal chemistry and material design.

In recent years, several novel halogenated liquids with characteristics of ionic liquids (ILs) were reported. To explore their performance in the absorption of CO(2), in this work, quantum chemical calculations at DFT level have been carried out to investigate halogen bonding interactions between experimentally available brominated ion pairs and CO(2) molecules. It is shown that, as compared to B3LYP, the functional PBE yields geometrical and energetic data more close to those of MP2 for cation-CO(2) systems. The cation of brominated ILs under study can interact with CO(2) molecules through Br···O interactions, possibly making an important impact on the physical solubility of CO(2) in brominated ILs. The optimized geometries of the complexes of the ion pair with CO(2) molecules are quite similar to those of the corresponding complexes of the cation, especially for the essentially linear C-Br···O contacts. However, much weaker halogen bonds are predicted in the former systems, as indicated by the longer intermolecular distances and the smaller interaction energies. Charges derived from NBO analysis reveal the origin of the different optimized conformations and halogen bonding interactions for the CO(2) molecule. Based on the electrostatic potential results, the substitution of hydrogen atoms with fluorine atoms constituting the cation is then applied to enhance halogen bond strength. The QTAIM analysis further validates the existence of halogen bonding interaction in all complexes. The topological properties at the halogen bond critical points indicate that the Br···O interactions in the complexes are basically electrostatic in nature and belong to conventional weak halogen bonds. This study would be helpful for designing new and effective ILs for CO(2) physical absorption.

Halogenation is an important approach in lead optimization for drug development and about half of the molecules used in high-throughput screening are halogenated. However, there is neither a suitable theoretical algorithm for evaluating the interaction between the halogen atoms of a ligand and its target protein nor a detailed understanding of how a halogen atom interacts with electron-rich atoms or groups of the residues in the binding pocket. In this Perspective, we concentrate on nonbonding interactions of halogens from both crystallographic data and theoretical viewpoints. It is found that organic halogen atoms are favorably involved in a wide variety of noncovalent protein-ligand interactions, such as halogen bonds C-X...O and hydrogen bonds C-X...H, that show remarkable differences in terms of the geometrical and energetic features. In biological molecules, heavier halogens prefer to form linear interactions with oxygen atoms and aromatic pi systems as compared to N or S, while the mean intermolecular distances for these types of halogen bonds increase with the radius or polarizability of halogen atoms, viz., Cl < Br < I. Furthermore, F...H interactions in protein-ligand complexes exhibit disparate behavior relative to X...H (X = Cl, Br, I) counterparts. These observed tendencies of the interactions involving halogens are subsequently rationalized by means of ab initio calculations using small model systems. The results presented herein should be of great use in the rational design of halogenated ligands as inhibitors and drugs as well as in biological engineering.

The hydrogen bond acceptor capability of halogens has long been underappreciated in the field of biology. In this work, we have surveyed structures of protein complexes with halogenated ligands to characterize geometrical preferences of C-X...H contacts and contributions of such interactions to protein-ligand binding affinity. Notably, F...H interactions in biomolecules exhibit a remarkably different behavior as compared to three other kinds of X...H (X = Cl, Br, I) interactions, which has been rationalized by means of ab initio calculations using simple model systems. The C-X...H contacts in biological systems are characterized as weak hydrogen bonding interactions. Furthermore, the electrophile "head on" and nucleophile "side on" interactions of halogens have been extensively investigated through the examination of interactions in protein structures and a two-layer ONIOM-based QM/MM method. In biomolecular systems, C-X...H contacts are recognized as secondary interaction contributions to C-X...O halogen bonds that play important roles in conferring specificity and affinity for halogenated ligands. The results presented here are within the context of their potential applications in drug design, including relevance to the development of accurate force fields for halogens.

Although recognized in small molecules for quite some time, the implications of halogen bonding in biomolecular systems are only now coming to light. In this study, several systems of proteins in complex with halogenated ligands have been investigated by using a two-layer QM/MM ONIOM methodology. In all cases, the halogen-oxygen distances are shown to be much less than the van der Waals radius sums. Single-point energy calculations unveil that the interaction becomes comparable in magnitude to classical hydrogen bonding. Furthermore, we found that the strength of the interactions attenuates in the order H approximately I > Br > Cl. These results agree well with the characteristics discovered within small model halogen-bonded systems. A detailed analysis of the interactions reveals that halogen bonding interactions are responsible for the different conformation of the molecules in the active site. This study would help to establish such interaction as a potential and effective tool in the context of drug design.

Triangular halogen trimers (RX)3, where X = Br, I and R represents H, H3C, H2FC, HF2C, F3C, CH2=CH, CH[triple bond]C, and Ph, have been investigated using the density functional theory in the Perdew, Burke, and Ernzerhof method. We report herein the optimized geometries of the stable structures, their vibrational frequencies, and binding energies with the two- and three-body terms. All trimer structures possess a cyclic array of halogen atoms in the type II approach by virtue of the nonspherical atomic charge distribution around the halogens. The Br...Br interactions in trimers are very weak, whereas the I...I interactions in trimers are relatively stronger. While all bromine trimers and most of iodine trimers are predicted to be noncooperative, three of iodine trimers show weak cooperativity. The analysis of vibration modes reveals that all halogen trimers exhibit no especially remarkable frequency shifts. It is also shown that the electrostatic contribution plays a major role in the halogen...halogen interactions in halogen trimers. In contrast to bromine trimers, the relative contribution of charge-transfer component to the halogen...halogen interactions becomes more important for iodine trimers.