Natalia Díaz - Academia.edu (original) (raw)

Papers by Natalia Díaz

Journal of Obesity, 2014

Cardiovascular diseases (CVD) represent about 30% of all global deaths. It is currently accepted ... more Cardiovascular diseases (CVD) represent about 30% of all global deaths. It is currently accepted that, in the atherogenic process, platelets play an important role, contributing to endothelial activation and modulation of the inflammatory phenomenon, promoting the beginning and formation of lesions and their subsequent thrombotic complications. The objective of the present work was to study using immunohistochemistry, the presence of platelets, monocytes/macrophages, and cell adhesion molecules (CD61, CD163, and CD54), in two stages of the atheromatous process. CF-1 mice fed a fat diet were used to obtain early stages of atheromatous process, denominated early stage of atherosclerosis, and ApoE−/−mice fed a fat diet were used to observe advanced stages of atherosclerosis. The CF-1 mice model presented immunostaining on endothelial surface for all three markers studied; the advanced atherosclerosis model in ApoE−/−mice also presented granular immunostaining on lesion thickness, for t...

Physical Chemistry Chemical Physics, 2019

Fluorine associated classical and quantum effects are quantified by the interacting quantum atoms... more Fluorine associated classical and quantum effects are quantified by the interacting quantum atoms method to identify the factors controlling the conformation in organofluorine molecules.

Chemphyschem : a European journal of chemical physics and physical chemistry, Apr 17, 2018

The interacting quantum atoms (IQA) method can assess, systematically and in great detail, the st... more The interacting quantum atoms (IQA) method can assess, systematically and in great detail, the strength and physics of both covalent and noncovalent interactions. The lack of a pair density in density functional theory (DFT), which precludes the direct IQA decomposition of the characteristic exchange-correlation energy, has been recently overcome by means of a scaling technique, which can largely expand the applicability of the method. To better assess the utility of the augmented IQA methodology to derive quantum chemical decompositions at the atomic and molecular levels, we report the results of Hartree-Fock (HF) and DFT calculations on the complexes included in the S66 and the ionic H-bond databases of benchmark geometry and binding energies. For all structures, we perform single-point and geometry optimizations using HF and selected DFT methods with triple-ζ basis sets followed by full IQA calculations. Pairwise dispersion energies are accounted for by the D3 method. We analyze ...

Journal of Chemical Theory and Computation, 2016

Human serum albumin undergoes reversible conformational transitions associated to ligand binding ... more Human serum albumin undergoes reversible conformational transitions associated to ligand binding or pH changes. Among them, the neutral to base (N→B) transition occurring between pH 7-9 seems to be relevant for its function as a carrier. Unfortunately, a detailed atomic model for the B-form is still lacking and several open questions remain concerning the charge distribution of the N-form. In this work, we report comparable molecular models for the N and B conformations that are built using continuum electrostatic calculations of pKa values and extended molecular dynamics (MD) simulations. Our computational models, which are critically assessed in terms of the available experimental observations relative to the N→B transition, reveal interesting similarities and differences between the N- and B-forms of HSA and highlight the importance of setting proper charge configurations in MD simulations.

Journal of computer-aided molecular design, 2016

Snake venom metalloproteinases are important toxins that play fundamental roles during envenomati... more Snake venom metalloproteinases are important toxins that play fundamental roles during envenomation. They share a structurally similar catalytic domain, but with diverse hemorrhagic capabilities. To understand the structural basis for this difference, we build and compare two dynamical models, one for the hemorrhagic atroxlysin-I from Bothrops atrox and the other for the non-hemorraghic leucurolysin-a from Bothrops leucurus. The analysis of the extended molecular dynamics simulations shows some changes in the local structure, flexibility and surface determinants that can contribute to explain the different hemorrhagic activity of the two enzymes. In agreement with previous results, the long Ω-loop (from residue 149 to 177) has a larger mobility in the hemorrhagic protein. In addition, we find some potentially-relevant differences at the base of the S1' pocket, what may be interesting for the structure-based design of new anti-venom agents. However, the sharpest differences in th...

Journal of Molecular Structure: THEOCHEM, 2009

Zinc-b-lactamases exhibit important differences in their mode of action that hamper the developme... more Zinc-b-lactamases exhibit important differences in their mode of action that hamper the development of effective inhibitors. This fact has prompted a considerable theoretical interest in these metalloenzymes in order to increase our knowledge at the molecular level. Herein, we present results from molecular dynamics (MD) simulations of the mononuclear BcII enzyme and its Michaelis complex with imipenem. Four protonation patterns of the active site were modeled in aqueous solution and their relative stability was estimated by means of linear-scaling semiempirical quantum mechanical (QM) energy calculations. Two binding modes of the imipenem substrate were examined: (a) the substrate interacts only with protein residues; (b) the b-lactam carbonyl group becomes a fifth ligand around the Zn ion. For the free enzyme, the energetically most stable configurations present a Zn-OH moiety, a neutral Asp 120 and a neutral His 263 residue. In contrast, for the complex formed between the BcII enzyme and imipenem, the energetic analyses predict that the configuration with a Zn-OH fragment and a doubly protonated His 263 residue becomes stabilized. Moreover, the MD simulations and energy calculations reveal that binding of the b-lactam carbonyl group to the Zn ion results in a proper enzyme/imipenem orientation for catalysis.

Journal of Chemical Theory and Computation, 2014

The extent and significance of conformational sampling is a major factor determining the reliabil... more The extent and significance of conformational sampling is a major factor determining the reliability of long-scale molecular simulations of large and flexible biomolecules. Although several methods have been proposed to quantify the effective sample size of molecular simulations by transforming root mean squared distances between pairs of configurations into statistical/probabilistic quantities, there is still no standard technique for measuring the size of sampling. In this work, we study conformational entropy (S conform) as a purely informational and probabilistic measure of sampling that does not require the adoption of any clustering protocol or distance metric between configurations. In addition S conform , which is calculated from the probability mass functions associated with discretized dihedral angles, offers other potential advantages for sampling assessment (e.g., global character, thermodynamic significance, relationship with internal degrees of freedom, etc.). The utility of S conform in sampling assessment is illustrated by carrying out test calculations on configurations produced by two extended molecular dynamics simulations, namely, a 2.0 μs trajectory of a highly flexible 17-residue peptide and the trajectory data set of the 1.0 ms bovine pancreatic trypsin inhibitor simulation provided by the D. E. Shaw research group.

Biochemistry, Jan 28, 2015

Collagen hydrolysis catalyzed by matrix metalloproteinases is an important and complex process in... more Collagen hydrolysis catalyzed by matrix metalloproteinases is an important and complex process involved in a variety of physiological and pathological conditions. To contribute to its characterization at the molecular level, herein we analyze three different models for the complex formed between the full-length matrix metalloproteinase-2 (MMP-2) enzyme and a synthetic triple-helical peptide (fTHP-5). The considered MMP-2/fTHP-5 complexes mainly differ in the location of the C-terminal hemopexin-like domain, but in all of them, the middle α-chain of the substrate (B-chain) is placed within the active site groove. We performed extended molecular dynamics (MD) simulations to determine the most likely rearrangements of the MMP-2 domains in response to the presence of the triple helix. The relative stability of the MD models is assessed in terms of molecular mechanics Poisson-Boltzmann calculations and approximate estimations of configurational entropy. In addition, the most significant ...

Theoretical Chemistry Accounts, 2010

Replacement of [Pd(H 2 O) 4 ] 2? by cis-[Pd(en) (H 2 O) 2 ] 2? , [PdCl 4 ] 2-, and [Pd(NH 3) 4 ] ... more Replacement of [Pd(H 2 O) 4 ] 2? by cis-[Pd(en) (H 2 O) 2 ] 2? , [PdCl 4 ] 2-, and [Pd(NH 3) 4 ] 2? on the hydrolytic cleavage of the Ace-Ala-Lys-Tyr-Gly-Gly-Met-Ala-Ala-Arg-Ala peptide is theoretically investigated by using different quantum chemical methods both in the gas phase an in water solution. First, we carry out a series of validation calculations on small Pd(II) complexes by computing highlevel ab initio [MP2 and CCSD(T)] and Density Functional Theory (B3LYP) electronic energies while solvent effects are taken into account by means of a Poisson-Boltzmann continuum model coupled with the B3LYP method. After having assessed the actual performance of the DFT calculations in predicting the stability constants for selected Pd(II)-complexes, we compute the relative free energies in solution of several Pd(II)-peptide model complexes. By assuming that the reaction of the peptide with cis-[Pd(en)(H 2 O) 2 ] 2? , [Pd(Cl) 4 ] 2-, and [Pd(NH 3) 4 ] 2? would lead to the initial formation of the respective peptide-bound complexes, which in turn would evolve to afford a hydrolytically active complex [Pd(peptide)(H 2 O) 2 ] 2? through the displacement of the en, Cl-, and NH 3 ligands by water, our calculations of the relative stability of these complexes allow us to rationalize why [Pd(H 2 O) 4 ] 2? and [Pd(NH 3) 4 ] 2? are more reactive than cis-[Pd(en)(H 2 O) 2 ] 2? and [PdCl 4 ] 2as experimentally found.

The Journal of Physical Chemistry B, 2006

The Journal of Physical Chemistry B, 2001

ABSTRACT

The Journal of Physical Chemistry B, 2008

Herein, we show that current methodologies in atomistic simulations can yield reliable standard f... more Herein, we show that current methodologies in atomistic simulations can yield reliable standard free energy values in aqueous solution for the transition from the dissociated monomeric form to the triple-helix state of collagen model peptides. The calculations are performed on a prototypical highly stable triple-helical peptide, [(Pro-Hyp-Gly) 10 ] 3 (POG10), and on the so-called T3-785 triple-helix mimicking a fragment from the type III human collagen, which is more thermally labile. On the basis of extensive MD simulations in explicit solvent followed by molecular-mechanical and electrostatic Poisson-Boltzmann calculations complemented with an accurate estimation of the nonpolar contributions to solvation, the computed free energy change for the aggregation processes of the POG10 and T3-785 peptides leading to their triple-helices is-6.6 and-6.1 kcal/mol, respectively. For POG10, this value is in agreement with differential scanning calorimetric data. However, it is shown that conformational entropy, which is estimated by means of an expansion of mutual information functions, preferentially destabilizes the triple-helical state of T3-785 by around 4.6 kcal/mol, thus explaining its lower thermal stability. Altogether, our computational results allow us to ascertain, for the first time, the actual thermodynamic forces controlling the absolute and relative stability of collagen model peptides.

The Journal of Physical Chemistry B, 2010

Hydrolytic cleavage of the oligopeptides Ace-Ala-Lys-Tyr-Gly approximately Gly-Met-Ala-Ala-Arg-Al... more Hydrolytic cleavage of the oligopeptides Ace-Ala-Lys-Tyr-Gly approximately Gly-Met-Ala-Ala-Arg-Ala and Ace-Lys-Gly-Gly-Ala-Gly approximately Pro-Met-Ala-Ala-Arg-Gly by [Pd(H(2)O)(4)](2+) was theoretically investigated by using molecular dynamics simulations and quantum mechanical calculations. The Pd anchorage to the peptide sequence is crucial to provoke the cleavage of the second bond upstream from the anchored methionine. For both cases, the most favorable reaction mechanism is a three-step route. The first step coincides with the experimental suggestion found for the Gly approximately Pro-Met sequence on a cleavage caused by an external attack of a water molecule to a complex in trans conformation of the scissile Gly approximately Gly and Gly approximately Pro peptide bonds. However, our results uncover the important role played by the presence of a Pd-coordinated water molecule, which simultaneously interacts with the carbonyl oxygen atom of the Gly amino acid in the Gly approximately Gly and Gly approximately Pro bonds. In accordance with experimental facts, the rise of the hydrolysis reaction rate when the Pro amino acid is located in the scissile peptide bond was also corroborated. The findings obtained at a molecular level from the present computations not only are relevant to rationalize the previously reported experiments but also could be of importance in designing new Pd(II) complexes for the regioselective cleavage of peptides and proteins.

The Journal of Physical Chemistry A, 2011

A set of benchmark results for the geometries, binding energies, and protonation affinities of 24... more A set of benchmark results for the geometries, binding energies, and protonation affinities of 24 complexes of small organic ligands with Ca(II) is provided. The chosen level of theory is CCSD(T)/CBS obtained by means of a composite procedure. The performance of four density functionals, namely, PW91, PBE, B3LYP, and TPSS and several Pople-type basis sets, namely, 6-31G(d), 6-31+G(d), 6-31+G(2d,p) and 6-311+G(d) have been assessed. Additionally, the nature of the metal ligand bonding has been analyzed by means of the Symmetry Adapted Perturbation Theory (SAPT). We have found that the B3LYP hybrid functional, in conjunction with either the polarized double-ζ 6-31+G(2d,p) or the triple-ζ 6-311+ G(d) basis sets, yields the closest results compared to the benchmark data. The SAPT analysis stresses the importance of induction effects in the binding of these complexes and suggests that consideration of classical electrostatic contributions alone may not be reliable enough for the prediction of relative binding energies for Ca(II) complexes.

Organic & Biomolecular Chemistry, 2013

Water solubility is a key aspect that needs to be addressed to obtain druglike compounds. In an e... more Water solubility is a key aspect that needs to be addressed to obtain druglike compounds. In an effort to improve the water solubility of our recently reported nanomolar matrix metalloproteinase type 2 (MMP-2) inhibitors based on triazole-substituted hydroxamates, we synthesized a new series of -sulfone, tetrahydropyran and -piperidine, -sulfone clicked hydroxamates and determined their inhibitory activities against both MMP-2 and MMP-9. The best results were found for 13e, a water-soluble compound that displays a low nanomolar activity against MMP-2 and is 26-fold less active against MMP-9. This finding allowed us to pursue in vitro permeability through Caco-2 monolayer and open the possibility for carrying out further preclinical investigations. Docking and MD simulations have been performed in order to rationalize the biological results. The inhibitory activity of this compound against a panel of ten MMPs was determined showing an interesting MMP-2/MMP-1,-8,-14 selectivity profile. The cytotoxicity and anti-invasive activity of the compounds on highly metastatic human fibrosarcoma tumor cells (HT1080) were determined, showing, at 10 M concentration, a decrease in cell invasiveness up to 80 %..

Journal of the American Chemical Society, 2003

Herein, we present results from molecular dynamics MD simulations (∼1 ns) of the TEM-1-lactamase ... more Herein, we present results from molecular dynamics MD simulations (∼1 ns) of the TEM-1-lactamase in aqueous solution. Both the free form of the enzyme and its complex with benzylpenicillin were studied. During the simulation of the free enzyme, the conformation of the Ω loop and the interresidue contacts defining the complex H-bond network in the active site were quite stable. Most interestingly, the water molecule connecting Glu166 and Ser70 does not exchange with bulk solvent, emphasizing its structural and catalytic relevance. In the presence of the substrate, Ser130, Ser235, and Arg244 directly interact with the-lactam carboxylate via H-bonds, whereas the Lys234 ammonium group has only an electrostatic influence. These interactions together with other specific contacts result in a very short distance (∼3 Å) between the attacking hydroxyl group of Ser70 and the-lactam ring carbonyl group, which is a favorable orientation for nucleophilic attack. Our simulations also gave insight into the possible pathways for proton abstraction from the Ser70 hydroxyl group. We propose that either the Glu166 carboxylate-Wat1 or the substrate carboxylate-Ser130 moieties could abstract a proton from the nucleophilic Ser70.

Journal of the American Chemical Society, 2004

To investigate the molecular details of the phosphoryl-transfer mechanism catalyzed by cAMPdepend... more To investigate the molecular details of the phosphoryl-transfer mechanism catalyzed by cAMPdependent protein kinase, we performed quantum mechanical (QM) calculations on a cluster model of the active site and molecular dynamics (MD) simulations of a ternary complex of the protein with Mg2ATP and a 20-residue peptide substrate. Overall, our theoretical results confirm the participation of the conserved aspartic acid, Asp 166, as an acid/base catalyst in the reaction mechanism catalyzed by protein kinases. The MD simulation shows that the contact between the nucleophilic serine side chain and the carboxylate group of Asp 166 is short and dynamically stable, whereas the QM study indicates that an Asp166-assisted pathway is structurally and energetically feasible and is in agreement with previous experimental results.

Journal of the American Chemical Society, 2000

Quantum chemical optimizations of the small model systems ([Zn(NH 3) 3 (H 2 O)] 2+ , [Zn(NH 3) 3 ... more Quantum chemical optimizations of the small model systems ([Zn(NH 3) 3 (H 2 O)] 2+ , [Zn(NH 3) 3 (OH)] + , [Zn(NH 3)(SH) (HCOO)(OH)]-1 (H 2 O) and [Zn(NH 3)(SH)(HCOO)(H 2 O)] (H 2 O)) were performed at different levels of quantum mechanical theory (HF/6-31G*, B3LYP/6-31G*, and MP2/6-31G*) to characterize the Znligand bonds for the Zn1 and Zn2 binding sites of metallo-lactamases. The nature of the zinc coordination environment was further studied by considering larger mononuclear complexes at the B3LYP/6-31G*//HF/ 6-31G* level of theory ([Zn(Me-Im) 3 (H 2 O)] 2+ , [Zn(Me-Im)(SCH 3)(CH 3 COO)(H 2 O)](H 2 O), etc.). The structure and properties of a series of binuclear model compounds showing an hydroxy-mediated Zn1‚‚‚Zn2 interaction were also analyzed at the same level of theory. One of the binuclear models with a global charge of +2, reproduces the main structural features of the Bacteroides fragilis active site as determined by X-ray crystallography. The proposed-lactamase model has a monoprotonated state characterized by a strong H-bond interaction between a zinc-shared water molecule and a Zn2-bound Asp carboxylic group. The theoretical results are discussed in the context of experimental kinetic and structural data on the B. fragilis active site, resulting in insights into the nature of the zinc-ligand interactions, the location of the mechanistically relevant water molecules, and the actual protonation state of the active site. By combining the present results with previous theoretical and experimental work, mechanistic details for the mode of action of zinc-lactamases are discussed.