Intraresidual Correlated Motions in Peptide Chains.

We investigate the interresidual and intraresidual correlations between dihedral displacements of adjacent residues within model polyalanine peptides by analyzing extensive molecular dynamics trajectories. Correlations are evaluated individually at different residue conformations covering the whole (ϕi,ψi)-space. From these, we draw maps that unveil an unprecedented strong intramolecular correlation displaying opposite (correlated/anticorrelated) behaviors at different conformations. Both interresidual and intraresidual correlations arise from the propensity of the peptide to minimize the overall atomic displacements.

Tuning the Optical Properties of Novel Antitumoral Drugs Based on Cyclometalated Iridium(III) Complexes.

Most of the current efforts in drug discovery are devoted to the design of molecules able to mitigate side effects by concentrating the biological action in the targeted tissue. One promising strategy is photodynamic therapy, which is based on the in situ generation of reactive singlet oxygen upon radiation exposure. However, such an approach requires the use of an efficient photosensitizer. This contribution deals with the optical properties of an Ir(III) complex, [Ir(pbz)2(N^N)] (pbz = 2-phenylbenzimidazole; N^N = methyl 1-butyl-2-pyridyl-benzimidazole-5-carboxylate), which has recently been shown to exhort a strong photoactivity, but still needs further improvements to reach clinical applications. We performed density functional theory calculations at the M06, PBE0, ωB97xD, and CAM-B3LYP levels to predict the impact of introducing electron donor-acceptor groups into the nature of the lowest excited states. The simulations performed demonstrate that the presence of a NH2 at the pbz ligand and a NO2 group at the N^N ligand yield a bathochromic shift of absorption spectrum. We report the most sensitive positions to tune the optical signatures of this family of complexes.

Antibodies as Carrier Molecules: Encapsulating Anti-Inflammatory Drugs inside Herceptine.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in about a third of breast cancer patients, with a strong involvement of the cyclooxygenase-2 (COX-2) enzyme in the tumor progress. HER2 and COX-2 are consequently potential targets for inhibiting carcionogenesis. Herceptin (trastuzumab) is an antibody that partially blocks HER2-positive cancers at their initial stage. Unfortunately, the overall response rate to the single treatment with this antibody is still modest, and therefore, it needs to be improved by combining several chemotherapeutic agents. On the other hand, nonsteroidal anti-inflammatory drugs (NSAIDs) are designed to halt COX-2 functionality, so they might also exhort an anticancer activity. In this contribution, dual Herceptin-NSAID drugs are designed using theoretical tools. More specifically, blind docking, molecular dynamics, and quantum calculations are performed to assess the stability of 14 NSAIDs embedded inside Herceptin. Our calculations reveal the feasibility of improving the antitumor activity of the parent Herceptin by designing a dual HER2-targeting with Etofenamate. That coupling mode might be used to further rationalize new clinical strategies beyond classical antibody dosages.

DFT Simulation of Structural and Optical Properties of 9-Aminoacridine Half-Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA.

In this work, we use DFT-based methods to simulate the chemical structures, optical properties, and interaction with DNA of a recently synthesized chelated C^N 9-aminoacridine arene Ru(II) anticancer agent and two new closely related Rh(III) and Ir(III) complexes using DFT-based methods. Four chemical models and a number of theoretical approaches, which representatively include the PBE0, B97D, ωB97X, ωB97X-D, M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and def2-TZVP basis sets, are tested. The best overall accuracy/cost performance for the optimization process is reached at the ωB97X-D/def2-SVP and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules (CHCl3) further refines the geometry, while taking into account the crystal network gives no significant improvements of the computed bond distances and angles. The analysis of the excited states reveals that the M06 level matches better the experimental absorption spectra, compared to ωB97X-D. The use of the M06/def2-SVP approach is therefore a well-balanced method to study theoretically the bioactivity of this type of antitumoral complexes, so we couple this TD-DFT approach to molecular dynamics simulations in order to assess their reactivity with DNA. The reported results demonstrate that these drugs could be used to inject electrons into DNA, which might broaden their applications in photoactivated chemotherapy and as new materials for DNA-based electrochemical nanodevices.

Structure, Spectra, and DFT Simulation of Nickel Benzazolate Complexes with Tris(2-aminoethyl)amine Ligand.

Benzazolate complexes of Ni(II), [Ni(pbz)(tren)]ClO4 (pbz = 2-(2'-hydroxyphenyl)-benzimidazole (pbm), 1, 2-(2'-hydroxyphenyl)-benzoxazole (pbx), 2, 2-(2'-hydroxyphenyl)-benzothiazole (pbt), 3; tren = tris(2-aminoethyl)amine), are prepared by self-assembly reaction and structurally characterized. Theoretical DFT simulations are carried out to reproduce the features of their crystal structures and their spectroscopic and photophysic properties. The three complexes are moderately luminescent at room temperature both in acetonitrile solution and in the solid state. The simulations indicate that the absorption spectrum is dominated by two well-defined transitions, and the electronic density concentrates in three MOs around the benzazole ligands. The Stokes shifts of the emission spectra of complexes 1-3 are determined by optimizing the electronic excited state.

Understanding the connection between conformational changes of peptides and equilibrium thermal fluctuations.

Despite the increasing evidence that conformational transitions in peptides and proteins are driven by specific vibrational energy pathways along the molecule, the current experimental techniques of analysis do as yet not allow to study these biophysical processes in terms of anisotropic energy flows. Computational methods offer a complementary approach to obtain a more detailed understanding of the vibrational and conformational dynamics of these systems. Accordingly, in this work we investigate jointly the vibrational energy distribution and the conformational dynamics of trialanine peptide in water solution at room temperature by applying the Instantaneous Normal Mode analysis to the results derived from equilibrium molecular dynamics simulations. It is shown that conformational changes in trialanine are triggered by the vibrational energy accumulated in the low-frequency modes of the molecule, and that excitation is caused exclusively by thermal fluctuations of the solute-solvent system, thus excluding the possibility of an intramolecular vibrational energy redistribution process.

Labelling Herceptin with a novel oxaliplatin derivative: a computational approach towards the selective drug delivery.

The clinical use of platinum(II)-based drugs has serious side effects due to the non-specific reactions with both malignant and normal cells. To circumvent such major drawback, novel metallodrugs might be combined with suitable carrier molecules, as antibodies, to ensure selective attacks on tumours while sparing healthy tissues. In this contribution, we investigate the stability of a novel oxaliplatin derivate drug embedded in Herceptin (trastuzumab), an antibody which is able to recognise breast cancer cells, by using a wide panel of theoretical tools: docking, molecular dynamics and quantum calculations. Our calculations reveal the binding mechanism: the drug initially interacts non-covalently with the Pro40A and Asp167A residues, and the nitrogen of His171B subsequently replaces one of the water molecules coordinated to the platinum center, where the latter step reversibly fixes the drug into the antibody. These data might be used to further rationalise the synthesis of improved drugs beyond classical platinum(II) derivatives by improving the ligand-protein coupling mode.

Structure and spectroscopic properties of nickel benzazolate complexes with hydrotris(pyrazolyl)borate ligand.

The reaction of benzazole ligands 2-(2'-hydroxylphenyl)benzimidazole (Hpbm), 2-(2'-hydroxylphenyl)benzoxazole (Hpbx), and 2-(2'-hydroxylphenyl)benzothiazole (Hpbt), with [Ni(Tp*)(µ-OH)]2 (Tp* = hydrotris(3,5-dimethylpyrazolyl)borate), leads to pentacoordinate nickel complexes [Ni(Tp*)(pbz)] (pbz = pbm (1), pbx (2), pbt (3)). The structures of 1, 2, and 3 were determined by X-ray crystallography. The pentacoordinate nickel complexes have distorted trigonal bipyramidal geometries with Addison's τ parameter values of 0.63, 0.73, and 0.61 for 1, 2 and 3, respectively. The benzazolates are bonded in an η(2)(N,O) fashion to the nickel atoms. DFT calculations are carried out to optimize the structures of the three complexes giving a good agreement with the X-ray structures. The (1)H NMR spectra of complexes 1-3 exhibit sharp isotropically shifted signals. The complete assignment of these signals required an application of two-dimensional {(1)H-(1)H}-COSY techniques. The experimental absorption spectra of the three complexes in chloroform solution each show an intense absorption band in the ultraviolet region ca. 240 nm, followed by three less intense bands, the first two at ∼295 and ∼340 nm, and the last more disperse one, at wavelengths between 360 and 410 nm. The absorption spectra are simulated by TD-DFT and reproduce the main features of the experimental spectra well. The analysis of the electronic transitions by inspection of the frontier molecular orbitals and also the natural transition orbitals allowed us to characterize and assign the observed bands properly. The three complexes are moderately blue luminescent at room temperature, both in the solid state and in solution. Emission spectra at room temperature display broad structureless bands in chloroform solution at 460, 482, and 512 nm for complexes 1, 2 and 3, respectively, and structured emission in solid state with λmax values of 473, 486, and 516 nm. Complexes containing different donor atoms in the benzazole ligand are furthermore observed to give different luminescence responses in the presence of Zn(II), Cd(II), Hg(II), and Cu(II).

Tratamiento quirurgico de la ulcera gastroduodenal: resultados retrospectivos; 115 casos / Surgical treatment of gastroduodenal ulcer: retrospective results; 115 casos

Se revisan 115 historias clínicas, entro los años 1978 y 1986, de los pacientes operados en el hospital N§ 2 de la C.N.S. en Cochabamba, Bolivia. La cirugía mas frecuente fue la gastrectomía (44%) seguida de la vagotomía supraseloectiva con un 25%. Presentaron úlcera duodenal el 71% de los operados, úlcera gástrica el 17% y la concomitancia de ambas en el 12% de los pacientes. Como patología asociada a la úlcera péptica, se observó reflujo gastroesofágico (8,6%) y colelitiasis (9,5%). La mortalidad operatoria, incluyendo las urgencias, fue de un 4,3%