A5019643670- Hemoglobin structure and function
- Protein Structure and Dynamics
- Spectroscopy and Quantum Chemical Studies
- Computational Drug Discovery Methods
- Heme Oxygenase-1 and Carbon Monoxide
- Cholinesterase and Neurodegenerative Diseases
- Photosynthetic Processes and Mechanisms
- Photochemistry and Electron Transfer Studies
- Free Radicals and Antioxidants
- Neonatal Health and Biochemistry
- Chemical synthesis and alkaloids
- Mass Spectrometry Techniques and Applications
- Hormonal Regulation and Hypertension
- Alzheimer's disease research and treatments
- Chemical Synthesis and Analysis
- Erythrocyte Function and Pathophysiology
- Eicosanoids and Hypertension Pharmacology
- Metabolism and Genetic Disorders
- Ion channel regulation and function
- Mitochondrial Function and Pathology
- Enzyme Structure and Function
- DNA and Nucleic Acid Chemistry
- Adenosine and Purinergic Signaling
- Porphyrin Metabolism and Disorders
- Physiological and biochemical adaptations
Universitat de Barcelona
2011-2023
Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes
2013
Université de Lorraine
2007-2013
Centre National de la Recherche Scientifique
2007-2013
Institució Catalana de Recerca i Estudis Avançats
2011
University of Buenos Aires
2007-2008
Universitat Autònoma de Barcelona
2008
Fundación Ciencias Exactas y Naturales
2007-2008
Consejo Nacional de Investigaciones Científicas y Técnicas
2007-2008
Zero to Three
2006
Abstract Motivation: A variety of pocket detection algorithms are now freely or commercially available to the scientific community for analysis static protein structures. However, since proteins dynamic entities, enhancing capabilities these programs straightforward and characterization cavities taking into account conformational ensembles should be valuable capturing plasticity pockets, therefore allow gaining insight structure–function relationships. Results: This article describes a new...
New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as new potent drugs that may simultaneously alleviate cognitive deficits behave disease-modifying agents by inhibiting the beta-amyloid (A beta) peptide aggregation through to both catalytic peripheral sites of enzyme. Particularly, compounds 5 6 emerged most heterodimers reported so far, displaying IC50 values for AChE inhibition 20 60 pM, respectively. More importantly, these inhibit...
A novel series of donepezil−tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites acetylcholinesterase (AChE) have been synthesized tested for their ability inhibit AChE, butyrylcholinesterase (BChE), AChE-induced Aβ aggregation. These compounds consist a unit tacrine or 6-chlorotacrine, which occupies same position as at AChE active site, 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety donepezil (or indane derivative thereof),...
We present a simple method for compression and management of very large molecular dynamics trajectories. The approach is based on the projection Cartesian snapshots collected along trajectory into an orthogonal space defined by eigenvectors obtained diagonalization covariance matrix. transformation mathematically exact when number equals 3N-6 (N being atoms), in practice accurate even much smaller, permitting dramatic reduction size files. In addition, we have examined ability method,...
A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic molecular modeling studies, results in a highly potent inhibition catalytic activity human AChE and, more importantly, vitro neutralization pathological chaperoning effect toward aggregation both β-amyloid peptide (Aβ) prion with key role protein. Huprine-tacrine take on added value that they...
Mycobacterium tuberculosis, the causative agent of human is forced into latency by nitric oxide produced macrophages during infection. In response to nitrosative stress M. tuberculosis has evolved a defense mechanism that relies on oxygenated form "truncated hemoglobin" N (trHbN), formally acting as NO-dioxygenase, yielding harmless nitrate ion. X-ray crystal structures have shown trHbN hosts two-branched protein matrix tunnel system, proposed control diatomic ligand migration heme,...
The most usual self-consistent reaction field (SCRF) continuum models for the description of solvation within quantum mechanical (QM) framework are reviewed, trying to emphasize their common roots as well inherent approximations assumed in calculation free energy solvation. Particular attention is also paid specific features involved development current state-of-the-art QM SCRF models. This used discuss need maintain a close correspondence between each formalism and details entailing its...
Mycobacterium tuberculosis truncated hemoglobin, HbN, is endowed with a potent nitric-oxide dioxygenase activity and has been found to relieve nitrosative stress enhance in vivo survival of heterologous host, Salmonella enterica Typhimurium, within the macrophages. These findings implicate involvement HbN defense M. against stress. The protein carries tunnel system composed short long branch that proposed facilitate diatomic ligand migration heme an unusual Pre-A motif at N terminus, which...
A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced self-induced β-amyloid (Aβ) aggregation β-secretase (BACE-1), cross the blood-brain barrier. The heterodimers consist a unit racemic or enantiopure huprine Y X donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as active peripheral mid-gorge-interacting moieties, respectively,...
In this study, we revisit the protocol previously proposed within framework of Miertus-Scrocco-Tomasi (MST) continuum model to define cavity between solute and solvent for predicting hydration free energies univalent ions. The relies on use a reduced (around 10-15% smaller than used neutral compounds) around atom(s) bearing formal charge. suitability approach is examined here series 47 ions which accurate experimental are available. Attention also paid effect charge renormalization correct...
Truncated hemoglobin-N is believed to constitute a defense mechanism of Mycobacterium tuberculosis against NO produced by macrophages, which converted the harmless nitrate anion. This process catalyzed very efficiently, as enzyme activity limited ligand diffusion. By using extended molecular dynamics simulations we explore that regulates diffusion and, particularly, role played residues assist binding O2 heme group. Our data strongly support hypothesis access cavity dynamically regulated...
Abstract The influence of pressure on the equilibrium between five‐(5c) and six‐coordination (6c) forms in neuroglobin (Ngb) myoglobin (Mb) has been examined by means molecular dynamics (MD) simulations at normal high pressure. results show that main effect is to reduce protein mobility without altering structure a significant manner. Moreover, our data suggest 5c 6c states globins largely controlled C‐D region. Finally, agreement with available experimental data, free energy profiles...
The main thrust of this investigation is the development models distributed atomic polarizabilities for treatment induction effects in molecular mechanics simulations. are obtained within framework induced dipole theory by fitting energies computed via a fast but accurate MP2/Sadlej-adjusted perturbational approach grid points surrounding molecule. Particular care paid examination quantities from implicitly and explicitly interacting polarizabilities. Appropriateness accuracy assessed...
The capability of Mycobacterium tuberculosis to rest in latency the infected organism appears be related disposal detoxification mechanisms, which converts nitric oxide (NO) produced by macrophages during initial growth infection stage into a nitrate anion. Such reaction associated with truncated hemoglobin N (trHbN). Even though previous experimental and theoretical studies have examined pathways used NO O2 access heme cavity, eggression pathway anion is still challenging question. In this...
The truncated hemoglobin N, HbN, of Mycobacterium tuberculosis is endowed with a potent nitric oxide dioxygenase (NOD) activity that allows it to relieve nitrosative stress and enhance in vivo survival its host. Despite small size, the protein matrix HbN hosts two-branched tunnel, consisting orthogonal short long channels, connects heme active site surface. A novel dual-path mechanism has been suggested drive migration O2 NO distal cavity. While oxygen migrates mainly by path, ligand-induced...
Abstract Nonsymbiotic hemoglobins AHb1 and AHb2 discovered in Arabidopsis thaliana are likely to carry out distinct physiological roles, consideration of their differences sequence, structure, expression pattern, tissue localization. Despite a relatively fast autoxidation the presence O 2 , we were able collect ‐binding curves for reduction enzymatic system. binds noncooperatively with p 50 0.021 ± 0.003 Torr, value consistent recently proposed role transport. The analysis internal cavities...
The distal His residue in type 1 nonsymbiotic hemoglobin AHb1 from Arabidopsis thaliana plays a fundamental role stabilizing the bound ligand. This might also be important regulating accessibility to cavity. feasibility of this functional has been examined using combination experimental and computational methods. We show that exchange CO between solvent reaction site is modulated by swinging motion His, which opens channel connects directly heme pocket with solvent. nearby PheB10 aids...
The synthesis of a new small library quinoxaline-containing peptides is described. After cytotoxic evaluation in four human cancer cell lines, as well detailed biological studies, it was found that the most active compound, RZ2, promotes formation acidic compartments, where accumulates, blocking progression autophagy. Further disruption mitochondrial membrane potential and an increase ROS observed, causing cells to undergo apoptosis. Given its activity protease-resistant features, RZ2 could...