Cooperative Self-Assembly Process Involving Giant Toroidal Polyoxometalate as a Membrane Building Block in Nanoscale Vesicles.

The self-assembly of organic amphiphilic species into various aggregates such as spherical or elongated micelles and cylinders up to the formation of lyotropic hexagonal or lamellar phases results from cooperative processes orchestrated by the hydrophobic effect, while those involving ionic inorganic polynuclear entities and nonionic organic components are still intriguing. Herein, we report on the supramolecular behavior of giant toroidal molybdenum blue-type polyoxometalate, namely, the {Mo154} species in the presence of n-octyl-ß-glucoside (C8G1), widely used as a surfactant in biochemistry. Structural investigations were carried out using a set of complementary multiscale methods including single-crystal X-ray diffraction analysis supported by molecular modeling, small-angle X-ray scattering and cryo-TEM observations. In addition, liquid NMR, viscosimetry, surface tension measurement, and isothermal titration calorimetry provided further information to decipher the complex aggregation pathway. Elucidation of the assembly process reveals a rich scenario where the presence of the large {Mo154} anion disrupts the self-assembly of the C8G1, well-known to produce micelles, and induces striking successive phase transitions from fluid-to-gel and from gel-to-fluid. Herein, intimate organic-inorganic primary interactions arising from the superchaotropic nature of the {Mo154} lead to versatile nanoscopic hybrid C8G1-{Mo154} aggregates including crystalline discrete assemblies, smectic lamellar liquid crystals, and large uni- or multilamellar vesicles where the large torus {Mo154} acts a trans-membrane component.

Expanding the Reticular Chemistry Building Block Library toward Highly Connected Nets: Ultraporous MOFs Based on 18-Connected Ternary, Trigonal Prismatic Superpolyhedra.

The chemistry of metal-organic frameworks (MOFs) continues to expand rapidly, providing materials with diverse structures and properties. The reticular chemistry approach, where well-defined structural building blocks are combined together to form crystalline open framework solids, has greatly accelerated the discovery of new and important materials. However, its full potential toward the rational design of MOFs relies on the availability of highly connected building blocks because these greatly reduce the number of possible structures. Toward this, building blocks with connectivity greater than 12 are highly desirable but extremely rare. We report here the discovery of novel 18-connected, trigonal prismatic, ternary building blocks (tbb's) and their assembly into unique MOFs, denoted as Fe-tbb-MOF-x (x: 1, 2, 3), with hierarchical micro- and mesoporosity. The remarkable tbb is an 18-c supertrigonal prism, with three points of extension at each corner, consisting of triangular (3-c) and rectangular (4-c) carboxylate-based organic linkers and trigonal prismatic [Fe3(µ3-Ο)(-COO)6]+ clusters. The tbb's are linked together by an 18-c cluster made of 4-c ligands and a crystallographically distinct Fe3(µ3-Ο) trimer, forming overall a 3-D (3,4,4,6,6)-c five nodal net. The hierarchical, highly porous nature of Fe-tbb-MOF-x (x: 1, 2, 3) was confirmed by recording detailed sorption isotherms of Ar, CH4, and CO2 at 87, 112, and 195 K, respectively, revealing an ultrahigh BET area (4263-4847 m2 g-1) and pore volume (1.95-2.29 cm3 g-1). Because of the observed ultrahigh porosities, the H2 and CH4 storage properties of Fe-tbb-MOF-x were investigated, revealing well-balanced high gravimetric and volumetric deliverable capacities for cryoadsorptive H2 storage (11.6 wt %/41.4 g L-1, 77 K/100 bar-160 K/5 bar), as well as CH4 storage at near ambient temperatures (367 mg g-1/160 cm3 STP cm-3, 5-100 bar at 298 K), placing these materials among the top performing MOFs. The present work opens new directions to apply reticular chemistry for the construction of novel MOFs with tunable porosities based on contracted or expanded tbb analogues.

A Fluorinated BODIPY-Based Zirconium Metal-Organic Framework for In Vivo Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT), an emergent noninvasive cancer treatment, is largely dependent on the presence of efficient photosensitizers (PSs) and a sufficient oxygen supply. However, the therapeutic efficacy of PSs is greatly compromised by poor solubility, aggregation tendency, and oxygen depletion within solid tumors during PDT in hypoxic microenvironments. Despite the potential of PS-based metal-organic frameworks (MOFs), addressing hypoxia remains challenging. Boron dipyrromethene (BODIPY) chromophores, with excellent photostability, have exhibited great potential in PDT and bioimaging. However, their practical application suffers from limited chemical stability under harsh MOF synthesis conditions. Herein, we report the synthesis of the first example of a Zr-based MOF, namely, 69-L2, exclusively constructed from the BODIPY-derived ligands via a single-crystal to single-crystal post-synthetic exchange, where a direct solvothermal method is not applicable. To increase the PDT performance in hypoxia, we modify 69-L2 with fluorinated phosphate-functionalized methoxy poly(ethylene glycol). The resulting 69-L2@F is an oxygen carrier, enabling tumor oxygenation and simultaneously acting as a PS for reactive oxygen species (ROS) generation under LED irradiation. We demonstrate that 69-L2@F has an enhanced PDT effect in triple-negative breast cancer MDA-MB-231 cells under both normoxia and hypoxia. Following positive results, we evaluated the in vivo activity of 69-L2@F with a hydrogel, enabling local therapy in a triple-negative breast cancer mice model and achieving exceptional antitumor efficacy in only 2 days. We envision BODIPY-based Zr-MOFs to provide a solution for hypoxia relief and maximize efficacy during in vivo PDT, offering new insights into the design of promising MOF-based PSs for hypoxic tumors.

Cavity-Directed Synthesis of Labile Polyoxometalates for Catalysis in Confined Spaces.

The artificial microenvironments inside coordination cages have gained significant attention for performing enzyme-like catalytic reactions by facilitating the formation of labile and complex molecules through a "ship-in-a-bottle" approach. Despite many fascinating examples, this approach remains scarcely explored in the context of synthesizing metallic clusters such as polyoxometalates (POMs). The development of innovative approaches to control and influence the speciation of POMs in aqueous solutions would greatly advance their applicability and could ultimately lead to the formation of elusive clusters that cannot be synthesized by using traditional methods. In this study, we employ host-guest stabilization within a coordination cage to enable a novel cavity-directed synthesis of labile POMs in aqueous solutions under mild conditions. The elusive Lindqvist [M6O19]2- (M=Mo or W) POMs were successfully synthesized at room temperature via the condensation of molybdate or tungstate building blocks within the confined cavity of a robust and water-soluble Pt6L4(NO3)12 coordination cage. Importantly, the encapsulation of these POMs enhances their stability in water, rendering them efficient catalysts for environmentally friendly and selective sulfoxidation reactions using H2O2 as a green oxidant in a pure aqueous medium. The approach developed in this paper offers a means to synthesize and stabilize the otherwise unstable metal-oxo clusters in water, which can broaden the scope of their applications.

Inorganic Drugs as a Tool for Protein Structure Solving and Studies on Conformational Changes.

Inorganic drugs are capable of tight interactions with proteins through coordination towards aminoacidic residues, and this feature is recognized as a key aspect for their pharmacological action. However, the "protein metalation process" is exploitable for solving the phase problem and structural resolution. In fact, the use of inorganic drugs bearing specific metal centers and ligands capable to drive the binding towards the desired portions of the protein target could represent a very intriguing and fruitful strategy. In this context, a theoretical approach may further contribute to solve protein structures and their refinement. Here, we delineate the main features of a reliable experimental-theoretical integrated approach, based on the use of metallodrugs, for protein structure solving.

Structure and Electronic Properties of Large Oligomeric Heterometallic 3d/CeIV Polyoxometalates.

Merging the rich chemistry of Ce(IV) polyoxometalates (POMs) with that of 3d polyanions remains a challenge due to the strong competition between these highly oxophilic lanthanide cations and 3d metallic ions for coordination to lacunary molecular metal oxides. We report herein the characterization of an unprecedented water stable hexameric CeIV/CoII POM (Ce12Co6) made of two {(SiW9)2Ce6} units connected to a {(SiW10)2Co6(PO4)2} core. In addition, the pentameric CeIV/NiII compound Ce6Ni8, where two {PW9Ni3W} and a {PW10Ni2} fragments are grafted on a {(PW9)2Ce6} moiety, has been obtained. Magnetic studies of Ce6Ni8 revealed ferromagnetic interactions between the NiII centers constituting the {Ni3PW10} fragments, in agreement with the geometry of such a trinuclear cluster. Related insoluble barium salts of Ce12Co6 and Ce6Ni8 were also prepared, allowing their solid-state electrochemical investigations and showing in particular that in Ce12Co6, both the cobalt, cerium, and silicotungstate moieties are electroactive. Finally, photophysical studies demonstrate the formation of long-lived reduced POMs photosensitized by [Ru(bpy)3]2+, suggesting that Ce12Co6 and Ce6Ni8 could be used as efficient reservoirs of reduction equivalents for photocatalytic reactions.

Chaotropic Effect as an Assembly Motif to Construct Supramolecular Cyclodextrin-Polyoxometalate-Based Frameworks.

In aqueous solution, low-charged polyoxometalates (POMs) exhibit remarkable self-assembly properties with nonionic organic matter that have been recently used to develop groundbreaking advances in host-guest chemistry, as well as in soft matter science. Herein, we exploit the affinity between a chaotropic POM and native cyclodextrins (α-, ß-, and γ-CD) to enhance the structural and functional diversity of cyclodextrin-based open frameworks. First, we reveal that the Anderson-Evans type polyoxometalate [AlMo6O18(OH)6]3- represents an efficient inorganic scaffold to design open hybrid frameworks built from infinite cyclodextrin channels connected through the disk-shaped POM. A single-crystal X-ray analysis demonstrates that the resulting supramolecular architectures contain large cavities (up to 2 nm) where the topologies are dictated by the rotational symmetry of the organic macrocycle, generating honeycomb (bnn net) and checkerboard-like (pcu net) networks for α-CD (C6) and γ-CD (C8), respectively. On the other hand, the use of ß-CD, a macrocycle with C7 ideal symmetry, led to a distorted-checkerboard-like network. The cyclodextrin-based frameworks built from an Anderson-Evans type POM are easily functionalizable using the molecular recognition properties of the macrocycle building units. As a proof of concept, we successfully isolated a series of compartmentalized functional frameworks by the entrapment of polyiodides or superchaotropic redox-active polyanions within the macrocyclic host matrix. This set of results paves the way for designing multifunctional supramolecular frameworks whose pore dimensions are controlled by the size of inorganic entities.

Structural Variety of Niobium(V) Polyoxo Clusters Obtained from the Reaction with Aromatic Monocarboxylic Acids: Isolation of {Nb2 O}, {Nb4 O4 } and {Nb8 O12 } Cores.

The reactivity of aryl monocarboxylic acids (benzoic, 1- or 2-naphtoic, 4'-methylbiphenyl-4-carboxylic, and anthracene-9-carboxylic acids) as complexing agents for the ethoxide niobium(V) (Nb(OEt)5 precursor has been investigated. A total of eight coordination complexes were isolated with distinct niobium(V) nuclearities as well as carboxylate complexation states. The use of benzoic acid gives a tetranuclear core Nb4 (µ2 -O)4 (L)4 (OEt)8 ] (L=benzoate (1)) with four Nb-(µ2 -O)-Nb linkages in a square plane configuration. A similar tetramer, 7, was obtained with 2-naphtoic acid by using a 55 % humid atmosphere synthetic route. Two types of dinuclear brick were identified with one central Nb-(µ2 -O)-Nb linkage; they differ in their complexation state, with one bridging carboxylate ([Nb2 (µ2 -O)(µ2 -OEt)(L)(OEt)6 ], with L=1-naphtoate (3) or anthracene-9-carboxylate (5)) or two bridging carboxylate groups ([Nb2 (µ2 -O)(L)2 (OEt)6 ], with L=4'-methylbiphenyl-4-carboxylic (4) or anthracene-9-carboxylate (6)). An octanuclear moiety [Nb8 (µ2 -O)12 (L)8 (η1 -L)4-x (OEt)4+x ] (with L=2-naphtoate, x=0 or 2; 8) was obtained by using a solvothermal route in acetonitrile; it has a cubic configuration with niobium centers at each node, linked by 12 µ2 -O groups. The formation of the niobium oxo clusters was characterized by infrared and liquid 1 H NMR spectroscopy in order to analyze the esterification reaction, which induces the release of water molecules that further react through oxolation with niobium atoms, in different {Nb2 O}, {Nb4 O4 } and {Nb8 O12 } nuclearities.

Host-Guest Complexation Between Cyclodextrins and Hybrid Hexavanadates: What are the Driving Forces?

Host-guest complexes between native cyclodextrins (α-, ß- and γ-CD) and hybrid Lindqvist-type polyoxovanadates (POVs) [V6 O13 ((OCH2 )3 C-R)2 ]2- with R = CH2 CH3 , NO2 , CH2 OH and NH(BOC) (BOC = N-tert-butoxycarbonyl) were studied in aqueous solution. Six crystal structures determined by single-crystal X-ray diffraction analysis revealed the nature of the functional R group strongly influences the host-guest conformation and also the crystal packing. In all systems isolated in the solid-state, the organic groups R are embedded within the cyclodextrin cavities, involving only a few weak supramolecular contacts. The interaction between hybrid POVs and the macrocyclic organic hosts have been deeply studied in solution using ITC, cyclic voltammetry and NMR methods (1D 1 H NMR, and 2D DOSY, and ROESY). This set of complementary techniques provides clear insights about the strength of interactions and the binding host-guest modes occurring in aqueous solution, highlighting a dramatic influence of the functional group R on the supramolecular properties of the hexavanadate polyoxoanions (association constant K1:1 vary from 0 to 2 000 M-1 ) while isolated functional organic groups exhibit only very weak intrinsic affinity with CDs. Electrochemical and calorimetric investigations suggest that the driving force of the host-guest association involving larger CDs (ß- and γ-CD) is mainly related to the chaotropic effect. In contrast, the hydrophobic effect supported by weak attractive forces appears as the main contributor for the formation of α-CD-containing host-guest complexes. In any cases, the origin of driving forces is clearly related to the ability of the macrocyclic host to desolvate the exposed moieties of the hybrid POVs.

Recognition determinants of broadly neutralizing human antibodies against dengue viruses.

Dengue disease is caused by four different flavivirus serotypes, which infect 390 million people yearly with 25% symptomatic cases and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies. We recently isolated human antibodies potently neutralizing all four dengue virus serotypes. Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell, explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.

Molecular basis for transfer RNA recognition by the double-stranded RNA-binding domain of human dihydrouridine synthase 2.

Double stranded RNA-binding domain (dsRBD) is a ubiquitous domain specialized in the recognition of double-stranded RNAs (dsRNAs). Present in many proteins and enzymes involved in various functional roles of RNA metabolism, including RNA splicing, editing, and transport, dsRBD generally binds to RNAs that lack complex structures. However, this belief has recently been challenged by the discovery of a dsRBD serving as a major tRNA binding module for human dihydrouridine synthase 2 (hDus2), a flavoenzyme that catalyzes synthesis of dihydrouridine within the complex elbow structure of tRNA. We here unveil the molecular mechanism by which hDus2 dsRBD recognizes a tRNA ligand. By solving the crystal structure of this dsRBD in complex with a dsRNA together with extensive characterizations of its interaction with tRNA using mutagenesis, NMR and SAXS, we establish that while hDus2 dsRBD retains a conventional dsRNA recognition capability, the presence of an N-terminal extension appended to the canonical domain provides additional residues for binding tRNA in a structure-specific mode of action. Our results support that this extension represents a feature by which the dsRBD specializes in tRNA biology and more broadly highlight the importance of structural appendages to canonical domains in promoting the emergence of functional diversity.

"Host in Host" Supramolecular Core-Shell Type Systems Based on Giant Ring-Shaped Polyoxometalates.

Herein, we show how the chaotropic effect arising from reduced molybdate ions in acidified aqueous solution is able to amplify drastically weak supramolecular interactions. Time-resolved Small Angle X-ray Scattering (SAXS) analysis suggests that molybdenum-blue oligomeric species form huge aggregates in the presence of γ-cyclodextrin (γ-CD) which results in the fast formation of nanoscopic {Mo154 }-based host-guest species, while X-ray diffraction analysis reveals that the ending-point of the scenario results in an unprecedented three-component well-ordered core-shell-like motif. A similar arrangement was found by using preformed hexarhenium chalcogenide-type cluster [Re6 Te8 (CN)6 ]4- as exogenous guest. This seminal work brings better understanding of the self-assembly processes in general and gives new opportunities for practical applications in the design of complex multicomponent materials via the simplicity of the non-covalent chemistry.

Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis.

Transthyretin (TTR) is a ß-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-ß, playing a protective role in Alzheimer's disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal.

An Institutional Review: Which Metrics Correlate With a Successful United States Medical Licensing Examination Step 1 Score?

PURPOSE: Since the introduction of the Comprehensive Basic Science Examination (CBSE) as an entrance examination in 2012, no studies have been performed correlating its relationship with passing rates on United States Medical Licensing Examination (USMLE) Step 1 in dental students. This study was designed to determine the impact of the CBSE score, dental grade point average (GPA), and undergraduate GPA on USMLE Step 1 performance and develop a CBSE cutoff score that correlates with a passing USMLE score. MATERIALS AND METHODS: A single-blinded, retrospective, cross-sectional study was designed. Data were collected from University of Alabama at Birmingham oral-maxillofacial surgery residents who had matriculated from 2014 to 2018. The primary predictor variable was the CBSE score. The primary outcome variable was the USMLE Step 1 score. Additional predictor variables included undergraduate and dental school GPAs. Bivariate statistics were calculated using a 2-tailed Pearson correlation (P = .05). Confounders were investigated using multivariate linear regression (P = .05). A bivariate linear regression was created using the variables of CBSE and USMLE scores. RESULTS: Dental school GPA and CBSE score correlated with USMLE Step 1 score (P < .05). Bivariate linear regression between CBSE and USMLE scores yielded a predictive equation of USMLE score = 2.02 × CBSE score + 66.2 (R2 = 0.30). When second-attempt scores were included, this equation became USMLE score = 2.08 × CBSE score + 67 (R2 = 0.49). The positive predictive value for a CBSE cutoff score of 61 reached 100% on repeated USMLE attempts. CONCLUSIONS: A CBSE score for dental students of 61 or greater correlates with a passing USMLE score and should be implemented to screen for dual-degree oral-maxillofacial surgery candidates.

Engineering Structural Dynamics of Zirconium Metal-Organic Frameworks Based on Natural C4 Linkers.

Engineering the structural flexibility of metal-organic framework (MOF) materials for separation-related applications remains a great challenge. We present here a strategy of mixing rigid and soft linkers in a MOF structure to achieve tunable structural flexibility, as exemplified in a series of stable isostructural Zr-MOFs built with natural C4 linkers (fumaric acid, succinic acid, and malic acid). As shown by the differences in linker bond stretching and bending freedom, these MOFs display distinct responsive dynamics to external stimuli, namely, changes in temperature or guest molecule type. Comprehensive in situ characterizations reveal a clear correlation between linker character and MOF dynamic behavior, which leads to the discovery of a multivariate flexible MOF. It shows an optimal combination of both good working capacity and significantly enhanced selectivity for CO2/N2 separation. In principle, it provides a new avenue for potentially improving the ability of microporous MOFs to separate other gaseous and liquid mixtures.

Redox-Active 1D Coordination Polymers of Iron-Sulfur Clusters.

Here we describe the combination of an archetypal redox-active metal sulfide cluster, Fe4S4, with an organic linker, 1,4-benzenedithiolate, to prepare coordination polymers containing infinite chains of Fe4S4 clusters. The crystal structures of two solid materials have been solved from synchrotron X-ray powder diffraction data using simulated annealing and refined by a least-squares Rietveld refinement procedure. The electronic properties of these chains have also been characterized by UV-visible and Mössbauer spectroscopies. Additional experiments demonstrated that these chains can be solubilized by variation of the countercation and that the chain structure is maintained in solution. The redox-activity of the Fe4S4 clusters can be accessed with chemical reagents. Introduction of charge carriers by reduction of the Fe4S4 clusters is found to increase the electrical conductivity of the materials by up to 4 orders of magnitude. These results highlight the utility of Fe4S4 clusters as redox-active building blocks in preparing new classes of coordination polymers.

MXCuBE2: the dawn of MXCuBE Collaboration.

MXCuBE2 is the second-generation evolution of the MXCuBE beamline control software, initially developed and used at ESRF - the European Synchrotron. MXCuBE2 extends, in an intuitive graphical user interface (GUI), the functionalities and data collection methods available to users while keeping all previously available features and allowing for the straightforward incorporation of ongoing and future developments. MXCuBE2 introduces an extended abstraction layer that allows easy interfacing of any kind of macromolecular crystallography (MX) hardware component, whether this is a diffractometer, sample changer, detector or optical element. MXCuBE2 also works in strong synergy with the ISPyB Laboratory Information Management System, accessing the list of samples available for a particular experimental session and associating, either from instructions contained in ISPyB or from user input via the MXCuBE2 GUI, different data collection types to them. The development of MXCuBE2 forms the core of a fruitful collaboration which brings together several European synchrotrons and a software development factory and, as such, defines a new paradigm for the development of beamline control platforms for the European MX user community.

Nonconventional Three-Component Hierarchical Host-Guest Assembly Based on Mo-Blue Ring-Shaped Giant Anion, γ-Cyclodextrin, and Dawson-type Polyoxometalate.

In this communication, we report on a noteworthy hybrid supramolecular assembly built from three functional components hierarchically organized through noncovalent interactions. The one-pot synthesis procedure leads to the formation of large Mo-blue ring-shaped anion {Mo154}, which contains the supramolecular adduct based on the symmetric encapsulation of the Dawson-type [P2W18O62]6- anion by two γ-cyclodextrin units. Such a nanoscopic onion-like structure, noted [P2W18O62]@2γ-CD@{Mo154} has been characterized by single-crystal X-ray diffraction, thus demonstrating the capability of the giant inorganic torus to develop relevant supramolecular chemistry, probing the strong affinity of the inner and outer faces of the γ-CD for the polyoxometalate surfaces. Furthermore, interactions and behavior in solution have been studied by multinuclear NMR spectroscopy, which supports specific interactions between γ-CD and POM units. Finally, the formation of this three-component hybrid assembly from one-pot procedure, in water and using nearly stoichiometric conditions, is discussed in terms of the driving forces orchestrating this highly efficient multilevel recognition process.

Comparison of helical scan and standard rotation methods in single-crystal X-ray data collection strategies.

X-ray radiation in macromolecular crystallography can chemically alter the biological material and deteriorate the integrity of the crystal lattice with concomitant loss of resolution. Typical alterations include decarboxylation of glutamic and aspartic residues, breaking of disulfide bonds and the reduction of metal centres. Helical scans add a small translation to the crystal in the rotation method, so that for every image the crystal is shifted to expose a fresh part. On beamline PROXIMA 2A at Synchrotron SOLEIL, this procedure has been tested with various parameters in an attempt to understand how to mitigate the effects of radiation damage. Here, the strategies used and the crystallographic metrics for various scenarios are reported. Among these, the loss of bromine from bromophenyl moieties appears to be a useful monitor of radiation damage as the carbon-bromine bond is very sensitive to X-ray irradiation. Two cases are focused on where helical scans are shown to be superior in obtaining meaningful data compared with conventional methods. In one case the initial resolution of the crystal is extended over time, and in the second case the anomalous signal is preserved to provide greater effective multiplicity and easier phasing.

Human TTR conformation altered by rhenium tris-carbonyl derivatives.

Transthyretin (TTR) is a 54 kDa homotetrameric serum protein that transports thyroxine (T4) and retinol. TTR is potentially amyloidogenic due to homotetramer dissociation into monomeric intermediates that self-assemble as amyloid deposits and insoluble fibrils. Most crystallographic structures, including those of amyloidogenic variants show the same tetramer without major variations in the monomer-monomer interface nor in the volume of the interdimeric cavity. Soaking TTR crystals in a solution containing rhenium tris-carbonyl derivatives yields a TTR conformer never observed before. Only one of the two monomers of the crystallographic dimer is significantly altered, and the inner part of the T4 binding cavity is expanded at one end and shrunk at the other. The result redefines the mechanism of allosteric communication between the two sites, suggesting that negative cooperativity is a function of dimer asymmetry, which can be induced through internal or external binding. An aspect that remains unexplained is why the conformational changes are ubiquitous throughout the crystal although the heavy metal content of the derivatized crystals is relatively low. The conformational changes observed, which include Leu(82), may represent a form of TTR better at scavenging ß-Amyloid. At a resolution of 1.69Å, with excellent refinement statistics and well defined electron density for all parts of the structure, it is possible to envisage answering important questions that range from protein cooperative behavior to heavy atom induced protein conformational modifications that can result in crystallographic non-isomorphism.