Nou avenç en l'estudi de l'Alzheimer

Investigadors de la UAB i de la Universitat d'Estocolm han modelat, per computador, la pèrdua d'estructura funcional de la proteïna apoE4 quan entra en contacte amb la molècula beta amiloide, principal causant de la malaltia d'Alzheimer. L'estudi, publicat a PLoS Computational Biology, dóna suport a evidències experimentals que vinculen l'apoE4 amb aquesta patologia i obre nous camps a explorar per entendre-la i combatre-la.Investigadores de la UAB y de la Universidad de Estocolmo han modelado por computador la pérdida de estructura funcional de la proteína apoE4 cuando entra en contacto con la molécula beta amiloide, principal causante de la enfermedad de Alzheimer. El estudio, publicado en PLoS Computational Biology, reafirma evidencias experimentales que vinculan la apoE4 con esta patología y abre nuevos campos a explorar para entenderla y combatirla.Researchers at UAB and University of Stockholm have created a computer modelling of the structural malfunctioning of the ApoE4 protein when it enters into contact with the Amyloid beta molecule, the main cause of Alzheimer's disease. The research, published in PLoS Computational Biology, supports experimental evidence that links ApoE4 with this pathology and opens up new exploration possibilities in understanding and fighting against the disease

AMH-RII : visió molecular de problemes hormonals en la diferenciació sexual

En l'esser humà, la sisena setmana del desenvolupament embrionari marca l'inici de la diferenciació dels conductes genitals. A l'embrió mascle, es genera una hormona que produeix la degeneració dels conductes de Müller (l'hormona anti-mülleriana AMH), sense l'acció repressora de la qual, aquests conductes portarien a la generació de les trompes i la matriu. Una part important de la repressió d'aquesta hormona es basa en processos de fixació a les membranes cel·lulars, gràcies a un receptor específic (l'AMH-RII). Qualsevol error en aquests processos que involucren tant a l'hormona com al seu receptor, pot donar lloc a un singular fenomen d'hermafroditisme. Un equip d'investigadors de la UAB ha pogut elaborar una modelització tridimensional del receptor de l'hormona, que facilita l'estudi de les diferents mutacions que pot patir i, per tant, la comprensió d'aquesta estranya malaltia genètica.En el ser humano, la sexta semana del desarrollo embrionario marca el inicio de la diferenciación de los conductos genitales. En el embrión masculino, se genera una hormona que produce la degeneració de los conductos de Müller (la hormona anti-mülleriana AMH), sin la acción represora de la cual, estos conductos llevarían a la generación de las trompes y la matriz. Una parte importante de la represión de esta hormona se basa en procesos de fijación en las membranas celulares, gracias a un receptor específico (el AMH-RII). Cualquier error en estos procesos que involucran tanto a la hormona como a su receptor, puede dar lugar a un singular fenómeno de hermafroditismo. Un equipo de investigadores de la UAB ha podido elaborar una modelización tridimensional del receptor de la hormona que facilitará el estudio de las diferentes mutaciones que puede sufrir y, por lo tanto, la comprensión de esta extraña enfermedad genética

Validation and Applications of Protein-Ligand Docking Approaches Improved for Metalloligands with Multiple Vacant Sites

Altres ajuts: COST Action CM1306Decoding the interaction between coordination compounds and proteins is of fundamental importance in biology, pharmacy, and medicine. In this context, protein-ligand docking represents a particularly interesting asset to predict how small compounds could interact with biomolecules, but to date, very little information is available to adapt these methodologies to metal-containing ligands. Here, we assessed the predictive capability of a metal-compatible parameter set for the docking program GOLD for metalloligands with multiple vacant sites and different geometries. The study first presents a benchmark of 25 well-characterized X-ray metalloligand-protein adducts. In 100% of the cases, the docking solutions are superimposable to the X-ray determination, and in 92% the value of the root-mean-square deviation between the experimental and calculated structures is lower than 1.5 Å. After the validation step, we applied these methods to five case studies for the prediction of the binding of pharmacological active metal species to proteins: (i) the anticancer copper(II) complex [Cu II (Br)(2-hydroxy-1-naphthaldehyde benzoyl hydrazine)(indazole)] to human serum albumin (HSA); (ii) one of the active species of antidiabetic and antitumor vanadium compounds, V IV O 2+ ion, to carboxypeptidase; (iii) the antiarthritic species [Au I (PEt 3 )] + to HSA; (iv) the antitumor oxaliplatin to ubiquitin; (v) the antitumor ruthenium(II) compound RAPTA-PentaOH to cathepsin B. The calculations suggested that the binding modes are in good agreement with the partial information retrieved from spectroscopic and spectrometric analysis and allowed us, in certain cases, to propose additional hypotheses. This method is an important update in protein-metalloligand docking, which could have a wide field of application, from biology and inorganic biochemistry to medicinal chemistry and pharmacology

Origin of the Rate Acceleration in the C−C Reductive Elimination from Pt(IV)-complex in a [Ga4L6]12− Supramolecular Metallocage

Altres ajuts: Acord transformatiu CRUE-CSICThe reductive elimination on [(MeP)Pt(MeOH)(CH)], 2P, complex performed in MeOH solution and inside a [GaL] metallocage are computationally analysed by mean of QM and MD simulations and compared with the mechanism of gold parent systems previously reported [EtPAu(MeOH)(CH)], 2Au. The comparative analysis between the encapsulated Au(III) and Pt(IV)-counterparts shows that there are no additional solvent MeOH molecules inside the cavity of the metallocage for both systems. The Gibbs energy barriers for the 2P reductive elimination calculated at DFT level are in good agreement with the experimental values for both environments. The effect of microsolvation and encapsulation on the rate acceleration are evaluated and shows that the latter is far more relevant, conversely to 2Au. Energy decomposition analysis indicates that the encapsulation is the main responsible for most of the energy barrier reduction. Microsolvation and encapsulation effects are not equally contributing for both metal systems and consequently, the reasons of the rate acceleration are not the same for both metallic systems despite the similarity between them

DFT Protocol for EPR prediction of paramagnetic Cu(II) complexes and application to protein binding sites

With the aim to provide a general protocol to interpret electron paramagnetic resonance (EPR) spectra of paramagnetic copper(II) coordination compounds, density functional theory (DFT) calculations of spin Hamiltonian parameters g and A for fourteen Cu(II) complexes with different charges, donor sets, and geometry were carried out using ORCA software. The performance of eleven functionals was tested, and on the basis of the mean absolute percent deviation (MAPD) and standard deviation (SD), the ranking of the functionals for Az is: B3LYP > B3PW91 ~ B3P86 > PBE0 > CAM-B3LYP > TPSSh > BH and HLYP > B2PLYP > MPW1PW91 > ω-B97x-D » M06; and for gz is: PBE0 > BH and HLYP > B2PLYP > ω-B97x-D > B3PW91~B3LYP~B3P86 > CAM-B3LYP > TPSSh~MPW1PW91 » M06. With B3LYP the MAPD with respect to A exp tl z is 8.6% with a SD of 4.2%, while with PBE0 the MAPD with respect to g exp tl z is 2.9% with a SD of 1.1%. The results of the validation confirm the fundamental role of the second order spin-orbit contribution to Az. The computational procedure was applied to predict the values of gz and Az of the adducts formed by Cu(II) with albumin and two fragments of prion protein, 106-126 and 180-193

Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid fibrils : Binding sites, structural stability, and possible physiological implications

One of Alzheimer's disease major hallmarks is the aggregation of β-amyloid peptide, a process in which metal ions play an important role. In the present work, an integrative computational study has been performed to identify the metal-binding regions and determine the conformational impact of Cu(II) and Al(III) ion binding to the β-amyloid (Aβ) fibrillary structure. Through classical and Gaussian accelerated molecular dynamics, it has been observed that the metal-free fiber shows a hinge fan-like motion of the S-shaped structure, maintaining the general conformation. Upon metal coordination, distinctive patterns are observed depending on the metal. Cu(II) binds to the flexible N-terminal region and induces structural changes that could ultimately disrupt the fibrillary structure. In contrast, Al(III) binding takes place with the residues Glu22 and Asp23, and its binding reinforces the core stability of the system. These results give clues on the molecular impact of the interaction of metal ions with the aggregates and sustain their non-innocent roles in the evolution of the illness

TALAIA : A 3D visual dictionary for protein structures

Motivation: Graphical analysis of the molecular structure of proteins can be very complex. Full-atom representations retain most geometric information but are generally crowded, and key structural patterns can be challenging to identify. Non-full-atom representations could be more instructive on physicochemical aspects but be insufficiently detailed regarding shapes (e.g. entity beans-like models in coarse grain approaches) or simple properties of amino acids (e.g. representation of superficial electrostatic properties). In this work, we present TALAIA a visual dictionary that aims to provide another layer of structural representations. TALAIA offers a visual grammar that combines simple representations of amino acids while retaining their general geometry and physicochemical properties. It uses unique objects, with differentiated shapes and colors to represent amino acids. It makes easier to spot crucial molecular information, including patches of amino acids or key interactions between side chains. Most conventions used in TALAIA are standard in chemistry and biochemistry, so experimentalists and modelers can rapidly grasp the meaning of any TALAIA depiction. Results: We propose TALAIA as a tool that renders protein structures and encodes structure and physicochemical aspects as a simple visual grammar. The approach is fast, highly informative, and intuitive, allowing the identification of possible interactions, hydrophobic patches, and other characteristic structural features at first glance. The first implementation of TALAIA can be found at https://github.com/insilichem/talaia

Modeling Kinetics and Thermodynamics of Guest Encapsulation into the [ML] 12- Supramolecular Organometallic Cage

Altres ajuts: Acord transformatiu CRUE-CSICThe encapsulation of molecular guests into supramolecular hosts is a complex molecular recognition process in which the guest displaces the solvent from the host cavity, while the host deforms to let the guest in. An atomistic description of the association would provide valuable insights on the physicochemical properties that guide it. This understanding may be used to design novel host assemblies with improved properties (i.e., affinities) toward a given class of guests. Molecular simulations may be conveniently used to model the association processes. It is thus of interest to establish efficient protocols to trace the encapsulation process and to predict the associated magnitudes Δ G and Δ G ⧧. Here, we report the calculation of the Gibbs energy barrier and Gibbs binding energy by means of explicit solvent molecular simulations for the [GaL] 12- metallocage encapsulating a series of cationic molecules. The Δ G ⧧ for encapsulation was estimated by means of umbrella sampling simulations. The steps involved were identified, including ion-pair formation and naphthalene rotation (from L ligands of the metallocage) during the guest's entrance. The Δ G values were computed using the attach-pull-release method. The results reveal the sensitivity of the estimates on the force field parameters, in particular on atomic charges, showing that higher accuracy is obtained when charges are derived from implicit solvent quantum chemical calculations. Correlation analysis identified some indicators for the binding affinity trends. All computed magnitudes are in very good agreement with experimental observations. This work provides, on one side, a benchmarked way to computationally model a highly charged metallocage encapsulation process. This includes a nonstandard parameterization and charge derivation procedure. On the other hand, it gives specific mechanistic information on the binding processes of [GaL] 12- at the molecular level where key motions are depicted. Taken together, the study provides an interesting option for the future design of metal-organic cages

Catalysis by [Ga4L6]12− metallocage on the Nazarov cyclization : the basicity of complexed alcohol is key

The Nazarov cyclization is investigated in solution and within K[GaL] supramolecular organometallic cage by means of computational methods. The reaction needs acidic condition in solution but works at neutral pH in the presence of the metallocage. The reaction steps for the process are analogous in both media: (a) protonation of the alcohol group, (b) water loss and (c) cyclization. The relative Gibbs energies of all the steps are affected by changing the environment from solvent to the metallocage. The first step in the mechanism, the alcohol protonation, turns out to be the most critical one for the acceleration of the reaction inside the metallocage. In order to calculate the relative stability of protonated alcohol inside the cavity, we propose a computational scheme for the calculation of basicity for species inside cavities and can be of general use. These results are in excellent agreement with the experiments, identifying key steps of catalysis and providing an in-depth understanding of the impact of the metallocage on all the reaction steps

Interaction of Vanadium(IV) Species with Ubiquitin : A Combined Instrumental and Computational Approach

Altres ajuts: COST Action CM1306The interaction of VIVO2+ ion and five VIVOL2 compounds with potential pharmacological application, where L indicates maltolate (ma), kojate (koj), acetylacetonate (acac), 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (dhp), and l-mimosinate (mim), with ubiquitin (Ub) was studied by EPR, ESI-MS, and computational (docking and DFT) methods. The free metal ion VIVO2+ interacts with Glu, Asp, His, Thr, and Leu residues, but the most stable sites (named 1 and 2) involve the coordination of (Glu16, Glu18) and (Glu24, Asp52). In the system with VIVOL2 compounds, the type of binding depends on the vanadium concentration. When the concentration is in the mM range, the binding occurs with cis-VOL2(H2O), L = ma, koj, dhp, and mim, or with VO(acac)2: in the first case, the equatorial coordination of His68, Glu16, Glu18, or Asp21 residues yields species with formula n[VOL2]-Ub where n = 2-3, while with VO(acac)2 only noncovalent surface interactions are revealed. When the concentration of V is on the order of micromolar, themono-chelated species VOL(H2O)2+ with L = ma, koj, acac, dhp, and mim, favored by the hydrolysis, interact with Ub, and adducts with composition n[VOL]-Ub (n = 1-2) are observed with the contemporaneous coordination of (Glu18, Asp21) or (Glu16, Glu18), and (Glu24, Asp52) or (Glu51, Asp52) donors. The results of this work suggest that the combined application of spectroscopic, spectrometric, and computational techniques allow the complete characterization of the ternary systems formed by a V compound and a model protein such as ubiquitin. The same approach can be applied, eventually changing the spectroscopic/spectrometric techniques, to study the interaction of other metal species with other proteins