Ligand Binding Strength Research Articles

Caught in the Act of Substitution: Interadsorbate Effects on an Atomically Precise Fe/Co/Se Nanocluster.

Directing groups guide substitution patterns in organic synthetic schemes, but little is known about pathways to control reactivity patterns, such as regioselectivity, in complex inorganic systems such as bioinorganic cofactors or extended surfaces. Interadsorbate effects are known to encode surface reactivity patterns in inorganic materials, modulating the location and binding strength of ligands. However, owing to limited experimental resolution into complex inorganic structures, there is little opportunity to resolve these effects on the atomic scale. Here, we utilize an atomically precise Fe/Co/Se nanocluster platform, [Fe3(L)2Co6Se8L'6]+ ([1(L)2]+; L = CN t Bu, THF; L' = Ph2PN(-)Tol), in which allosteric interadsorbate effects give rise to pronounced site-differentiation. Using a combination of spectroscopic techniques and single-crystal X-ray diffractometry, we discover that coordination of THF at the ligand-free Fe site in [1(CN t Bu)2]+ sets off a domino effect wherein allosteric through-cluster interactions promote the regioselective dissociation of CN t Bu at a neighboring Fe site. Computational analysis reveals that this active site correlation is a result of delocalized Fe···Se···Co···Se covalent interactions that intertwine edge sites on the same cluster face. This study provides an unprecedented atom-scale glimpse into how interfacial metal-support interactions mediate a collective and regiospecific path for substrate exchange across multiple active sites.

Different receptor models show differences in ligand binding strength and location: a computational drug screening for the tick-borne encephalitis virus.

The tick-borne encephalitis virus (TBE) is a neurotrophic disease that has spread more rapidly throughout Europe and Asia in the past few years. At the same time, no cure or specific therapy is known to battle the illness apart from vaccination. To find a pharmacologically relevant drug, a computer-aided drug screening was initiated. Such a procedure probes a possible binding of a drug to the RNA Polymerase of TBE. The crystal structure of the receptor, however, includes missing and partially modeled regions, which rendered the structure incomplete and of questionable use for a thorough drug screening procedure. The quality of the receptor model was addressed by studying three putative structures created. We show that the choice of receptor models greatly influences the binding affinity of potential drug molecules and that the binding location could also be significantly impacted. We demonstrate that some drug candidates are unsuitable for one model but show decent results for another. Without any prejudice on the three employed receptor models, the study reveals the imperative need to investigate the receptor structure before drug binding is probed whether experimentally or computationally.

Data-driven discovery of active phosphine ligand space for cross-coupling reactions.

The design of highly active catalysts is a main theme in organic chemistry, but it still relies heavily on expert experience. Herein, powered by machine-learning global structure exploration, we forge a Metal-Phosphine Catalyst Database (MPCD) with a meticulously designed ligand replacement energy metric, a key descriptor to describe the metal-ligand interactions. It pushes the rational design of organometallic catalysts to a quantitative era, where a ±10 kJ mol-1 window of relative ligand binding strength, a so-called active ligand space (ALS), is identified for highly effective catalyst screening. We highlight the chemistry interpretability and effectiveness of ALS for various C-N, C-C and C-S cross-coupling reactions via a Sabatier-principle-based volcano plot and demonstrate its predictive power in discovering low-cost ligands in catalyzing Suzuki cross-coupling involving aryl chloride. The advent of the MPCD provides a data-driven new route for speeding up organometallic catalysis and other applications.

Synthesis and biological evaluation of 2′-hydroxychalcone derivatives as AMPK activators

A series of 2′-hydroxychalcone derivatives with various substituents on B-ring were synthesized and evaluated for AMP-activated protein kinase (AMPK) activation activity in podocyte cells. The results displayed that hydroxy, methoxy and methylenedioxy groups on B-ring could enhance the activitiy better than O-saturated alkyl, O-unsaturated alkyl or other alkoxy groups. Compounds 27 and 29 possess the highest fold change of 2.48 and 2.73, respectively, which were higher than those of reference compound (8) (1.28) and metformin (1.88). Compounds 27 and 29 were then subjected to a concentration–response study to obtain the EC50 values of 2.0 and 4.8 µM, respectively and MTT assays also showed that cell viability was not influenced by the exposure of podocytes to compounds 27 and 29 at concentrations up to 50 μM. In addition, compound 27 was proved to activate AMPK via calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-dependent pathway without affecting intracellular calcium levels. The computational study showed that the potent compounds exhibited stronger ligand-binding strength to CaMKKβ, particularly compounds 27 (−8.4 kcal/mol) and 29 (−8.0 kcal/mol), compared to compound 8 (-7.5 kcal/mol). Fragment molecular orbital (FMO) calculation demonstrated that compound 27 was superior to compound 29 due to the presence of methyl group, which amplified the binding by hydrophobic interactions. Therefore, compound 27 would represent a promising AMPK activator for further investigation of the treatment of diabetes and diabetic nephropathy.

Metal-Ligand Interactions and Their Roles in Controlling Nanoparticle Formation and Functions.

ConspectusFunctional nanoparticles (NPs) have been studied extensively in the past decades for their unique nanoscale properties and their promising applications in advanced nanosciences and nanotechnologies. One critical component of studying these NPs is to prepare monodisperse NPs so that their physical and chemical properties can be tuned and optimized. Solution phase reactions have provided the most reliable processes for fabricating such monodisperse NPs in which metal-ligand interactions play essential roles in the synthetic controls. These interactions are also key to stabilizing the preformed NPs for them to show the desired electronic, magnetic, photonic, and catalytic properties. In this Account, we summarize some representative organic bipolar ligands that have recently been explored to control NP formation and NP functions. These include aliphatic acids, alkylphosphonic acids, alkylamines, alkylphosphines, and alkylthiols. This ligand group covers metal-ligand interactions via covalent, coordination, and electrostatic bonds that are most commonly employed to control NP sizes, compositions, shapes, and properties. The metal-ligand bonding effects on NP nucleation rate and growth can now be more thoroughly investigated by in situ spectroscopic and theoretical studies. In general, to obtain the desired NP size and monodispersity requires rational control of the metal/ligand ratios, concentrations, and reaction temperatures in the synthetic solutions. In addition, for multicomponent NPs, the binding strength of ligands to various metal surfaces needs to be considered in order to prepare these NPs with predesigned compositions. The selective ligand binding onto certain facets of NPs is also key to anisotropic growth of NPs, as demonstrated in the synthesis of one-dimensional nanorods and nanowires. The effects of metal-ligand interactions on NP functions are discussed in two aspects, electrochemical catalysis for CO2 reduction and electronic transport across NP assemblies. We first highlight recent advances in using surface ligands to promote the electrochemical reduction of CO2. Several mechanisms are discussed, including the modification of the catalyst surface environment, electron transfer through the metal-organic interface, and stabilization of the CO2 reduction intermediates, all of which facilitate selective CO2 reduction. These strategies lead to better understanding of molecular level control of catalysis for further catalyst optimization. Metal-ligand interaction in magnetic NPs can also be used to control tunneling magnetoresistance properties across NPs in NP assemblies by tuning NP interparticle spacing and surface spin polarization. In all, metal-ligand interactions have yielded particularly promising directions for tuning CO2 reduction selectivity and for optimizing nanoelectronics, and the concepts can certainly be extended to rationalize NP engineering at atomic/molecular precision for the fabrication of sensitive functional devices that will be critical for many nanotechnological applications.

Detailed phenotypic and functional characterization of CMV-associated adaptive NK cells in rhesus macaques.

Previous research on adaptive NK cells in rhesus macaques suffered from the lack of specific antibodies to differentiate between inhibitory CD94/NKG2A and stimulatory CD94/NKG2C heterodimeric receptors. Recently we reported an expansion of NKG2C receptor-encoding genes in rhesus macaques, but their expression and functional role on primary NK cells remained unknown due to this deficit. Thus, we established monoclonal antibodies 4A8 and 7B1 which show identical specificities and bind to both NKG2C-1 and NKG2C-2 but neither react with NKG2C-3 nor NKG2A on transfected cells. Using a combination of 4A8 and Z199 antibodies in multicolor flow cytometry we detected broad expression (4-73%) of NKG2C-1 and/or NKG2C-2 (NKG2C-1/2) on primary NK cells in rhesus macaques from our breeding colony. Stratifying our data to CMV-positive and CMV-negative animals, we noticed a higher proportion (23-73%) of primary NK cells expressing NKG2C-1/2 in CMV+ as compared to CMV- macaques (4-5%). These NKG2C-1/2-positive NK cells in CMV+ macaques are characterized by lower expression of IL12RB2, ZBTB16, SH2D1B, but not FCER1G, as well as high expression of IFNG, indicating that antibody 4A8 detects CMV-associated adaptive NK cells. Single cell RNA seq data of 4A8-positive NK cells from a rhCMV-positive macaque demonstrated that a high proportion of these adaptive NK cells transcribe in addition to NKG2C-1 and NKG2C-2 also NKG2C-3, but interestingly NKG2A as well. Remarkably, in comparison to NKG2A, NKG2C-1 and in particular NKG2C-2 bind Mamu-E with higher avidity. Primary NK cells exposed to Mamu-E-expressing target cells displayed strong degranulation as well as IFN-gamma expression of 4A8+ adaptive NK cells from rhCMV+ animals. Thus, despite co-expression of inhibitory and stimulatory CD94/NKG2 receptors the higher number of different stimulatory NKG2C receptors and their higher binding avidity to Mamu-E outreach inhibitory signaling via NKG2A. These data demonstrate the evolutionary conservation of the CMV-driven development of NKG2C-positive adaptive NK cells with particular molecular signatures in primates and with changes in gene copy numbers and ligand-binding strength of NKG2C isotypes. Thus, rhesus macaques represent a suitable and valuable nonhuman primate animal model to study the CMV-NKG2C liaison in vivo.

Challenges of Measuring Soluble Mn(III) Species in Natural Samples.

Soluble Mn(III)–L complexes appear to constitute a substantial portion of manganese (Mn) in many environments and serve as critical high-potential species for biogeochemical processes. However, the inherent reactivity and lability of these complexes—the same chemical characteristics that make them uniquely important in biogeochemistry—also make them incredibly difficult to measure. Here we present experimental results demonstrating the limits of common analytical methods used to quantify these complexes. The leucoberbelin-blue method is extremely useful for detecting many high-valent Mn species, but it is incompatible with the subset of Mn(III) complexes that rapidly decompose under low-pH conditions—a methodological requirement for the assay. The Cd-porphyrin method works well for measuring Mn(II) species, but it does not work for measuring Mn(III) species, because additional chemistry occurs that is inconsistent with the proposed reaction mechanism. In both cases, the behavior of Mn(III) species in these methods ultimately stems from inter- and intramolecular redox chemistry that curtails the use of these approaches as a reflection of ligand-binding strength. With growing appreciation for the importance of high-valent Mn species and their cycling in the environment, these results underscore the need for additional method development to enable quantifying such species rapidly and accurately in nature.

Fe-binding organic ligands in coastal and frontal regions of the western Antarctic Peninsula

Abstract. Organic ligands are a key factor determining the availability of dissolved iron (DFe) in the high-nutrient low-chlorophyll (HNLC) areas of the Southern Ocean. In this study, organic speciation of Fe is investigated along a natural gradient of the western Antarctic Peninsula, from an ice-covered shelf to the open ocean. An electrochemical approach, competitive ligand exchange – adsorptive cathodic stripping voltammetry (CLE-AdCSV), was applied. Our results indicated that organic ligands in the surface water on the shelf are associated with ice-algal exudates, possibly combined with melting of sea ice. Organic ligands in the deeper shelf water are supplied via the resuspension of slope or shelf sediments. Further offshore, organic ligands are most likely related to the development of phytoplankton blooms in open ocean waters. On the shelf, total ligand concentrations ([Lt]) were between 1.2 and 6.4 nM eq. Fe. The organic ligands offshore ranged between 1.0 and 3.0 nM eq. Fe. The southern boundary of the Antarctic Circumpolar Current (SB ACC) separated the organic ligands on the shelf from bloom-associated ligands offshore. Overall, organic ligand concentrations always exceeded DFe concentrations (excess ligand concentration, [L′] = 0.8–5.0 nM eq. Fe). The [L′] made up to 80 % of [Lt], suggesting that any additional Fe input can be stabilized in the dissolved form via organic complexation. The denser modified Circumpolar Deep Water (mCDW) on the shelf showed the highest complexation capacity of Fe (αFe'L; the product of [L′] and conditional binding strength of ligands, KFe'Lcond). Since Fe is also supplied by shelf sediments and glacial discharge, the high complexation capacity over the shelf can keep Fe dissolved and available for local primary productivity later in the season upon sea-ice melting.

The Effects of Temperature and Pressure on Protein-Ligand Binding in the Presence of Mars-Relevant Salts

Simple SummaryInteractions of ligands with proteins are central to all reactions in the biological cell. How such reactions are affected by harsh environmental conditions, such as low temperatures, high pressures, and high concentrations of biologically destructive salts, is still largely unknown. Our work focused on specific salts found on Mars to understand whether the planet’s potentially liquid, water-rich subsurface harbors conditions that are theoretically favorable for life. Our data show that, while magnesium chloride and sulfate do not significantly alter protein–ligand interactions, the perchlorate ion strongly affects protein–ligand binding. However, the temperature and pressure conditions encountered on Mars do not necessarily preclude protein–ligand interactions of the type studied here.Protein–ligand interactions are fundamental to all biochemical processes. Generally, these processes are studied at ambient temperature and pressure conditions. We investigated the binding of the small ligand 8-anilinonaphthalene-1-sulfonic acid (ANS) to the multifunctional protein bovine serum albumin (BSA) at ambient and low temperatures and at high pressure conditions, in the presence of ions associated with the surface and subsurface of Mars, including the chaotropic perchlorate ion. We found that salts such as magnesium chloride and sulfate only slightly affect the protein–ligand complex formation. In contrast, magnesium perchlorate strongly affects the interaction between ANS and BSA at the single site level, leading to a change in stoichiometry and strength of ligand binding. Interestingly, both a decrease in temperature and an increase in pressure favor the ligand binding process, resulting in a negative change in protein–ligand binding volume. This suggests that biochemical reactions that are fundamental for the regulation of biological processes are theoretically possible outside standard temperature and pressure conditions, such as in the harsh conditions of the Martian subsurface.

CLIFF: A component-based, machine-learned, intermolecular force field

Computation of intermolecular interactions is a challenge in drug discovery because accurate ab initio techniques are too computationally expensive to be routinely applied to drug-protein models. Classical force fields are more computationally feasible, and force fields designed to match symmetry adapted perturbation theory (SAPT) interaction energies can remain accurate in this context. Unfortunately, the application of such force fields is complicated by the laborious parameterization required for computations on new molecules. Here, we introduce the component-based machine-learned intermolecular force field (CLIFF), which combines accurate, physics-based equations for intermolecular interaction energies with machine-learning models to enable automatic parameterization. The CLIFF uses functional forms corresponding to electrostatic, exchange-repulsion, induction/polarization, and London dispersion components in SAPT. Molecule-independent parameters are fit with respect to SAPT2+(3)δMP2/aug-cc-pVTZ, and molecule-dependent atomic parameters (atomic widths, atomic multipoles, and Hirshfeld ratios) are obtained from machine learning models developed for C, N, O, H, S, F, Cl, and Br. The CLIFF achieves mean absolute errors (MAEs) no worse than 0.70kcal mol-1 in both total and component energies across a diverse dimer test set. For the side chain-side chain interaction database derived from protein fragments, the CLIFF produces total interaction energies with an MAE of 0.27kcal mol-1 with respect to reference data, outperforming similar and even more expensive methods. In applications to a set of model drug-protein interactions, the CLIFF is able to accurately rank-order ligand binding strengths and achieves less than 10% error with respect to SAPT reference values for most complexes.

Diverse Native Ensembles Dictate the Differential Functional Responses of Nuclear Receptor Ligand-Binding Domains.

Native states of folded proteins are characterized by a large ensemble of conformations whose relative populations and interconversion dynamics determine the functional output. This is more apparent in transcription factors that have evolved to be inherently sensitive to small perturbations, thus fine-tuning gene expression. To explore the extent to which such functional features are imprinted on the folding landscape of transcription factor ligand-binding domains (LBDs), we characterize paralogous LBDs of the nuclear receptor (NR) family employing an energetically detailed and ensemble-based Ising-like statistical mechanical model. We find that the native ensembles of the LBDs from glucocorticoid receptor, PPAγ, and thyroid hormone receptor display a remarkable diversity in the width of the native wells, the number and nature of partially structured states, and hence the degree of conformational order. Monte Carlo simulations employing the full state representation of the ensemble highlight that many of the functional conformations coexist in equilibrium, whose relative populations are sensitive to both temperature and the strength of ligand binding. Allosteric modulation of the degree of structure at a coregulator binding site on ligand binding is shown to arise via a redistribution of populations in the native ensembles of glucocorticoid and PPAγ LBDs. Our results illustrate how functional requirements can drive the evolution of conformationally diverse native ensembles in paralogs.

Exploring the Iron‐Binding Potential of the Ocean Using a Combined pH and DOC Parameterization

The major part of dissolved iron (DFe) in seawater is bound to organic matter, which prevents iron from adsorptive removal by sinking particles and essentially regulates the residence time of DFe and its availability for marine biota. Characteristics of iron‐binding ligands highly depend on their biological origin and physico‐chemical properties of seawater which may intensely alter under ongoing climate change. To understand environmental controls on the iron binding, we applied a function of pH and dissolved organic carbon (DOC) to describe changes in the binding strength of organic ligands in a global biogeochemical model (REcoM). This function was derived based on calculations using a thermodynamic chemical speciation model NICA. This parameterization considerably improved the modeled DFe distribution, particularly in the surface Pacific and the global mesopelagic and deep waters, compared to our previous model simulations with a constant ligand or one prognostic ligand. This indicates that the organic binding of iron is apparently controlled by seawater pH in addition to its link to organic matter. We tested further the response of this control to environmental changes in a simulation with future pH of a high emission scenario. The response of the binding potential shows a complex pattern in different regions and is regulated by factors that have opposite effects on the binding potential. The relative contributions of these factors can change over time by a continual change of environmental conditions. A dynamic feedback system therefore needs to be considered to predict the marine iron cycle under ongoing climate change.

Natural Fe-binding organic ligands in Fram Strait and over the northeast Greenland shelf

There is a paucity of data on Fe-binding ligands in the Arctic Ocean. Here we investigate the distribution and chemical properties of natural Fe-binding ligands in Fram Strait and over the northeast Greenland shelf, shedding light on their potential sources and transport. Our results indicate that the main sources of organic ligands to surface waters of Fram Strait included primary productivity and supply from the Arctic Ocean. We calculated the mean total Fe-binding ligand concentration, [Lt], in Polar Surface Water from the western Fram Strait to be 1.65 ± 0.4 nM eq. Fe. This value is in between reported values for the Arctic and North Atlantic Oceans, confirming reports of north to south decreases in [Lt] from the Arctic Ocean. The differences between ligand sources in different biogeochemical provinces, resulted in distinctive ligand properties and distributions that are reflected in [Lt], binding strength (log KFe'L′) and competing strength (log αFe'L) of ligands. Higher [Lt] was present near the Nioghalvfjerdsfjorden (79 N) Glacier terminus and in the Westwind Trough (median of [Lt] = 2.17 nM eq. Fe; log KFe'L′ = 12.3; log αFe'L = 3.4) than in the Norske Trough (median of [Lt] = 1.89 nM eq. Fe; log KFe'L′= 12.8; log αFe'L = 3.8) and in Fram Strait (median of [Lt] = 1.38 nM eq. Fe; log KFe'L′ = 13; log αFe'L= 3.9). However, organic ligands near the 79 N Glacier terminus and in the Westwind Trough were weaker, and therefore less reactive than organic ligands in the Norske Trough and in Fram Strait. These weaker ligands, although more abundant than in the Fram Strait, reduce overall Fe solubility in waters transported from the 79N Glacier to Fram Strait. The lower ligand binding strength in the outflow results in a higher inorganic Fe concentration, [Fe´], which is more prone to precipitation and/or scavenging than Fe complexed with stronger ligands. Ongoing changes in the Arctic and sub-Arctic Oceans will influence both terrestrially derived and in-situ produced Fe-binding ligands, and therefore will have consequences for Fe solubility and availability to microbial populations and Fe cycling in Fram Strait.

The Interaction of Curcumin and Rosmarinic Acid with Non‐Amyloid‐Component Domain of Alpha‐Synuclein: A Molecular Dynamics Study

AbstractOne notable phenomenon in the Parkinson's disease (PD) treatment is the identification of inhibitors of the self‐assembly of Alpha‐Synuclein (AS) protein. Here, the interactions of two herbal compounds of Curcumin (CUR) and Rosmarinic‐acid (RA) with the NAC domain of AS were investigated by the molecular dynamics (MD) simulation method. More specifically, the purpose of this study was to investigate the molecular aspects and the inhibition mechanism of the considered molecules, as well as evaluating their effectiveness in preventing the AS aggregation process. The trajectories of MD simulations were used to evaluate the structural properties of the simulated systems and to infer qualitative and quantitative facts regarding the interactions between the considered ligands and the NAC domains. In addition to the MD studies, the energetics of the ligand‐NAC domain interactions were studied by MM‐PBSA method. The free energy of binding and various contributions to it, as modeled in the MM‐PBSA method, were evaluated and analyzed. The results were also analyzed in terms of the rate and strength of ligand binding to the domains. These analyses showed that RA could bind to the NAC domain faster, as compared to CUR, while the latter binds to the domain more strongly than the former does. However, overall, the results imply that both CUR and RA could effectively bind to NAC domains; so, they could be considered as candidates to reduce the aggregation of AS or as potential drugs for PD.

Effect of the Ligand Binding Strength on the Morphology of Functionalized Gold Nanoparticles.

Functionalized gold nanoparticles are investigated by density functional theory calculations in the context of cancer radiotherapy. Several typical experimental shapes, including nanostars, nanospheres, and nanorods, are modeled by optimizing Au clusters covered by organic monolayers composed of hydrated short-chain polyethylene glycol (PEG) ligands. The PEGylation stabilizes significantly the stellation of decahedral Au54 by deforming significantly its geometry at the spikes. The higher stability of the PEG molecules adsorbed on this stellated nanocluster with respect to the more spherical icosahedral Au55 and truncated octahedral Au79 leads to a larger energy cost to desorb them and thus a weaker propensity for the starred nanoparticle to exchange ligands with the cell membrane, in agreement with experiments. These results open interesting possibilities for advancing our understanding of the cellular uptake of gold nanoparticles.

Metal-ligand bond strength determines the fate of organic ligands on the catalyst surface during the electrochemical CO2 reduction reaction.

Colloidally synthesised nanocrystals (NCs) are increasingly utilised as catalysts to drive both thermal and electrocatalytic reactions. Their well-defined size and shape, controlled by organic ligands, are ideal to identify the parameters relevant to the activity, selectivity and stability in catalysis. However, the impact of the native surface ligands during catalysis still remains poorly understood, as does their fate. CuNCs are among the state-of-the-art catalysts for the electrochemical CO2 reduction reaction (CO2RR). In this work, we study CuNCs that are capped by different organic ligands to investigate their impact on the catalytic properties. We show that the latter desorb from the surface at a cathodic potential that depends on their binding strength with the metal surface, rather than their own electroreduction potentials. By monitoring the evolving surface chemistry in situ, we find that weakly bound ligands desorb very rapidly while strongly bound ligands impact the catalytic performance. This work provides a criterion to select labile ligands versus ligands that will persist on the surface, thus offering opportunity for interface design.

Ligand Binding Strength Explains the Distribution of Iron in the North Atlantic Ocean

AbstractObservations of dissolved iron (dFe) in the subtropical North Atlantic revealed remarkable features: While the near‐surface dFe concentration is low despite receiving high dust deposition, the subsurface dFe concentration is high. We test several hypotheses that might explain this feature in an ocean biogeochemistry model with a refined Fe cycling scheme. These hypotheses invoke a stronger lithogenic scavenging rate, rapid biological uptake, and a weaker binding between Fe and a ubiquitous, refractory ligand. While the standard model overestimates the surface dFe concentration, a 10‐time stronger biological uptake run causes a slight reduction in the model surface dFe. A tenfold decrease in the binding strength of the refractory ligand, suggested by recent observations, starts reproducing the observed dFe pattern, with a potential impact for the global nutrient distribution. An extreme value for the lithogenic scavenging rate can also match the model dFe with observations, but this process is still poorly constrained.

Multiscale model of integrin adhesion assembly

The ability of adherent cells to form adhesions is critical to numerous phases of their physiology. The assembly of adhesions is mediated by several types of integrins. These integrins differ in physical properties, including rate of diffusion on the plasma membrane, rapidity of changing conformation from bent to extended, affinity for extracellular matrix ligands, and lifetimes of their ligand-bound states. However, the way in which nanoscale physical properties of integrins ensure proper adhesion assembly remains elusive. We observe experimentally that both β-1 and β-3 integrins localize in nascent adhesions at the cell leading edge. In order to understand how different nanoscale parameters of β-1 and β-3 integrins mediate proper adhesion assembly, we therefore develop a coarse-grained computational model. Results from the model demonstrate that morphology and distribution of nascent adhesions depend on ligand binding affinity and strength of pairwise interactions. Organization of nascent adhesions depends on the relative amounts of integrins with different bond kinetics. Moreover, the model shows that the architecture of an actin filament network does not perturb the total amount of integrin clustering and ligand binding; however, only bundled actin architectures favor adhesion stability and ultimately maturation. Together, our results support the view that cells can finely tune the expression of different integrin types to determine both structural and dynamic properties of adhesions.

An overview about the impact of hinge region towards the anticancer binding affinity of the Ck2 ligands: a quantum chemical analysis

Casein kinase 2 (CK2) is extremely preserved and universally uttered serine/threonine kinase, vital for cellular feasibility. The present study aimed to analyse the binding strength of CK2 ligands specifically in the hinge region, as it is aware that most of the existing drugs are targeted to bind the hinge of the corresponding protein. The analysis will give a clear picture about the role of hinge region with ligand, which will be useful for scientist community in drug designing. To predict the binding strength of CK2 ligands, the role of halogen bond, hydrogen bond interaction at the hinge region was depicted in detail through interaction energy calculations at M062Z/def2-QZVP level of theory. Highest occupied molecular orbital (HOMO) map plotted for CK2 ligands gives a clear pictorial representation of orbitals, which induce for interaction. Ligand properties discussed in detail through Lipinski’s five rules predict that almost all the ligands satisfy the rule, except 3KXG, which violates Lipinski’s two rules, i.e. molecular mass exceeds 500 Da, i.e. 512.61 Da, and Log P value is high of 5.09. The natural bond orbital analysis deliberates that the hydrogen/halogen bonds figuring out within the complexes are observed to have moderate stabilization energy, but those hydrogen/halogen bonds that exist with close contacts have high stabilization energy. Overall, this computational work will give an understandable depiction for modelling anticancer ligands along the hinge region in CK2 protein; also, it will give a new path for the choice of side chains on the ligand.Communicated by Ramaswamy H. Sarma

Multiple roles for O-glycans in Notch signalling.

Notch signalling regulates a plethora of developmental processes and is also essential for the maintenance of tissue homeostasis in adults. Therefore, fine-tuning of Notch signalling strength needs to be tightly regulated. Of key importance for the regulation of Notch signalling are O-fucose, O-GlcNAc and O-glucose glycans attached to the extracellular domain of Notch receptors. The EGF repeats of the Notch receptor extracellular domain harbour consensus sites for addition of the different types of O-glycan to Ser or Thr, which takes place in the endoplasmic reticulum. Studies from Drosophila to mammals have demonstrated the multifaceted roles of O-glycosylation in regulating Notch signalling. O-glycosylation modulates different aspects of Notch signalling including recognition by Notch ligands, the strength of ligand binding, Notch receptor trafficking, stability and activation at the cell surface. Defects in O-glycosylation of Notch receptors give rise to pathologies in humans. This Review summarizes the nature of the O-glycans on Notch receptors and their differential effects on Notch signalling.