The Permeation mechanism of cisplatin through a dioleoylphosphocholine bilayer

The investigation of the intermolecular interactions between platinum-based anticancer drugs and lipid bilayers is of special relevance to unveil the mechanisms involved in different steps of the anticancer mode of action of these drugs. We have simulated the permeation of cisplatin through a model membrane composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids by means of umbrella sampling classical molecular dynamics simulations. The initial physisorption of cisplatin into the polar region of the lipid membrane is controlled, in a first moment, by long-range electrostatic interactions with the choline groups and, in a second step, by long-range electrostatic and hydrogen bond interactions with the phosphate groups. The second half of the permeation pathway, in which cisplatin diffuses through the nonpolar region of the bilayer, is characterized by the drop of the interactions with the polar heads and the rise of attractive interactions with the non-polar tails, which are dominated by van der Waals contributions

Effect of stacking interactions on charge transfer states in photoswitches interacting with ion channels

The activity of ion channels can be reversibly photo-controlled via the binding of molecular photoswitches, often based on an azobenzene scaffold. Those azobenzene derivatives interact with aromatic residues of the protein via stacking interactions. In the present work, the effect of face-to-face and t-shaped stacking interactions on the excited state electronic structure of azobenzene and p-diaminoazobenzene integrated into the Na V1.4 channel is computationally investigated. The formation of a charge transfer state, caused by electron transfer from the protein to the photoswitches, is observed. This state is strongly red shifted when the interaction takes place in a face-to-face orientation and electron donating groups are present on the aromatic ring of the amino acids. The low-energy charge transfer state can interfere with the photoisomerization process after excitation to the bright state by leading to the formation of radical species. </p

An Efficient Multilayer Approach to Model DNA-Based Nanobiosensors

In this work, we present a full computational protocol to successfully obtain the one-electron reduction potential of nanobiosensors based on a self-assembled monolayer of DNA nucleobases linked to a gold substrate. The model is able to account for conformational sampling and environmental effects at a quantum mechanical (QM) level efficiently, by combining molecular mechanics (MM) molecular dynamics and multilayer QM/MM/continuum calculations within the framework of Marcus theory. The theoretical model shows that a guanine-based biosensor is more prone to be oxidized than the isolated nucleobase in water due to the electrostatic interactions between the assembled guanine molecules. In addition, the redox properties of the biosensor can be tuned by modifying the nature of the linker that anchor the nucleobases to the metal supportThis work was partially supported by the MICINN − Spanish Ministry of Science and Innovation − Project Nos. PID2019-110091GB-I00 and PID2020-117806GA-I00, funded by MCIN/AEI/10.13039/ 501100011033, and the “María de Maeztu” (No. CEX2018- 000805-M) Program for Centers of Excellence in R&D. J.J.N. acknowledge the Comunidad de Madrid for funding through the Attraction of Talent Program (Grant Ref. No. 2018-T1/ BMD-10261). J.L.T. acknowledges the FPU-2019 grant from the Spanish Ministry of Universit

Intramolecular and intermolecular hole delocalization rules the reducer character of isolated nucleobases and homogeneous single-stranded DNA

The use of DNA strands as nanowires or electrochemical biosensors requires a deep understanding of charge transfer processes along the strand, as well as of the redox properties. These properties are computationally assessed in detail throughout this study. By applying molecular dynamics and hybrid QM/continuum and QM/QM/continuum schemes, the vertical ionization energies, adiabatic ionization energies, vertical attachment energies, one-electron oxidation potentials, and delocalization of the hole generated upon oxidation have been determined for nucleobases in their free form and as part of a pure single-stranded DNA. We show that the reducer ability of the isolated nucleobases is explained by the intramolecular delocalization of the positively charged hole, while the enhancement of the reducer character when going from aqueous solution to the strand correlates very well with the intermolecular hole delocalization. Our simulations suggest that the redox properties of DNA strands can be tuned by playing with the balance between intramolecular and intermolecular charge delocalizationThis work was partially supported by the MICINN – Spanish Ministry of Science and Innovation – Projects PID2019-110091GB-I00 and PID2020-117806GA-I00 funded by MCIN/AEI/10.13039/501100011033, and the ‘María de Maeztu’ (CEX2018-000805-M) Program for Centers of Excellence in R & D. J. J. N. acknowledge the Comunidad de Madrid for funding through the Attraction of Talent Program (Grant ref.2018-T1/BMD-10261). J. L. T. acknowledges the FPU19/02292 grant from the Spanish Ministry of Universit

In silico investigation of the photoisomerization mechanism of push-push azoderivatives

The design of novel chromophores showing specific photophysical traits is nowadays crucial for the development of new dyes and optical devices. Azobenzene derivatives comprise the largest fraction of industrial dyes and remain one of the main functions to be employed in the design of general-purpose photoactivated switches. In this context, we have investigated the optical and photoisomerization properties of two push-push azo derivatives, from a purely theoretical perspective, to outline a mechanistic landscape that can contribute to setting the grounds for the future goal of formulating dyes with specific photophysical properties. Both derivatives show downhill excited-state potential energy surfaces, hinting at fast photoactivated isomerization. In addition, both the trans and cis forms show nearly complementary absorption spectra leading to discriminatory color and differential excitation possibilities. Additionally, the reverse cis to trans ground state thermal isomerization reactions show higher energy barriers than the parent azobenzene molecule, supporting their potential use in different technological applicationsRamón y Cajal Program. Ministerio de Ciencia e Innovación (Grant: RYC-2016-20489). Ministerio de Ciencia e Innovación of Spain (PID2021-125207NBC31 and PID2020-117806 GA-I00). Comunidad de Madrid (Grant ref 2018-T1/BMD-10261

Implementación de algoritmos meméticos con capacidad de auto-generación sobre CouchBD

Los algoritmos meméticos constituyen un paradigma de optimización basado en la explotación sistemática del conocimiento acerca del problema que se desea resolver y de la combinación de ideas tomadas de diferentes metaheurísticas, tanto basadas en población como basadas en búsqueda local. Como la mayoría de los algoritmos evolutivos, los meméticos también han sido usados para resolver problemas de optimización en el campo de la Inteligencia Artificial, gracias a su capacidad de explorar espacios de búsqueda complejos en tiempos razonables. En este artículo se presenta una propuesta de implementación de algoritmos multimeméticos (esto es, algo- ritmos meméticos con capacidad de auto-generar las estrategias de búsqueda local) que emplea el sistema de Base de Datos CouchDB para manejar poblaciones persistentes y se hace un análisis del rendimiento que muestran estos algoritmos al resolver algunos problemas de optimización.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Este trabajo está parcialmente financiado por la Junta de Andalucía dentro del proyecto P10-TIC-6083 (DNEMESIS), por el MICINN dentro del proyecto TIN2011-28627-C04 (ANYSELF

Challenges in simulating light-induced processes in DNA

© 2016 by the authors; licensee MDPI, Basel, Switzerland. In this contribution, we give a perspective on the main challenges in performing theoretical simulations of photoinduced phenomena within DNA and its molecular building blocks. We distinguish the different tasks that should be involved in the simulation of a complete DNA strand subject to UV irradiation: (i) stationary quantum chemical computations; (ii) the explicit description of the initial excitation of DNA with light; (iii) modeling the nonadiabatic excited state dynamics; (iv) simulation of the detected experimental observable; and (v) the subsequent analysis of the respective results. We succinctly describe the methods that are currently employed in each of these steps. While for each of them, there are different approaches with different degrees of accuracy, no feasible method exists to tackle all problems at once. Depending on the technique or combination of several ones, it can be problematic to describe the stacking of nucleobases, bond breaking and formation, quantum interferences and tunneling or even simply to characterize the involved wavefunctions. It is therefore argued that more method development and/or the combination of different techniques are urgently required. It is essential also to exercise these new developments in further studies on DNA and subsystems thereof, ideally comprising simulations of all of the different components that occur in the corresponding experiments

Binding of azobenzene and p-diaminoazobenzene to the human voltage-gated sodium channel Nav1.4

The activity of voltage-gated ion channels can be controlled by the binding of photoswitches inside their internal cavity and subsequent light irradiation. We investigated the binding of azobenzene and p-diaminoazobenzene to the human Nav1.4 channel in the inactivated state by means of Gaussian accelerated molecular dynamics simulations and free-energy computations. Three stable binding pockets were identified for each of the two photoswitches. In all the cases, the binding is controlled by the balance between the favorable hydrophobic interactions of the ligands with the nonpolar residues of the protein and the unfavorable polar solvation energy. In addition, electrostatic interactions between the ligand and the polar aminoacids are also relevant for p-diaminoazobenzene due to the presence of the amino groups on the benzene moieties. These groups participate in hydrogen bonding in the most favorable binding pocket and in long-range electrostatic interactions in the other pockets. The thermodinamically preferred binding sites found for both photoswitches are close to the selectivity filter of the channel. Therefore, it is very likely that the binding of these ligands will induce alterations in the ion conduction through the channel

Variabilidade geográfica da razão mortalidade/incidência por cancro da mama no sul da Europa

O cancro da mama é o segundo carcinoma mais frequente constituindo a principal causa de mortalidade por carcinoma em mulheres (Ferlay et al., 2013). Detecção e intervenção precoce e qualidade do tratamento influenciam a mortalidade por esta patologia (Bastos, Peleteiro, Gouveia, Coleman, & Lunet, 2010). A percentagem da razão de Mortalidade/Incidência (%RMI) avalia o acesso a rastreios e a qualidade das terapeuticas, apresentando valores baixos se a mortalidade é baixa para os casos incidentes reportados. (Sunkara & Hebert, 2015). Objetivo: Avaliar a variabilidade na %RMI por cancro da mama (número de óbitos por cada 100 casos incidentes de cancro da mama) em quatro países do sul da Europa culturalmente próximos: Espanha, Portugal, Grécia e Itália. Metodologia: Através da International Agency for Research on Cancer (IARC), obtiveram-se casos observados em 2012 (incidentes e óbitos) para cada país em estudo em mulheres com 15-39, 40-49, 50-64, 65-74 e 75 ou mais anos (WHO, 2016). Obtiveram-se valores de %RMI por país e faixa etária dividindo o número de óbitos pelo número de casos incidentes e multiplicando por 100. Os respetivos intervalos de confiança a 95% (IC95%) foram obtidos pelo teste exato de Fisher. Resultados: Considerando os quatro países como um todo, verifica-se que a %RMI para cancro da mama (número de óbitos por cada 100 casos incidentes) é de 8%, 12%, 17%, 24% e 55%, respectivamente em mulheres com 15-39, 40-49, 50-64, 65-74 e 75 ou mais anos. Verifica-se variabilidade entre países para este indicador, mas não em todas as faixas etárias. Para mulheres mais jovens, Portugal apresenta %RMI de 8,7% (IC95%:6,5-11,3) muito semelhante aos outros três países. Em mulheres com idades entre 40-49 anos e 50-64 anos a %RMI observada em Portugal é, respectivamente, 13,6% (IC95%:11,6-15,8) e 19,7% (IC95%:18,0-21,5), notoriamente inferior à observada na Grécia mas mais elevada em relação a Espanha e Itália. Em mulheres com 65-74 e 75 ou mais anos, as %RMI observadas em Portugal foram, respectivamente, 27,4% (IC95%:24,9-30,1) e 52,5% (IC95%:49,7-55,3), muito semelhantes ao que se observa em Espanha e Itália. Conclusões: Embora em mulheres mais jovens o número de óbitos por cada 100 casos incidentes de cancro da mama seja inferior a 10, este valor é superior a 50 nas mulheres mais velhas. De acordo com os resultados há variabilidade geográfica na %RMI mas esta variabilidade não é transversal a todas as faixas etárias. Os resultados sugerem que o acesso a diagnóstico precoce e a efectividade de tratamento diferem entre países, mas que esta relação é modificada pela idade. Os resultados sugerem equacionar as estratégias preventivas adaptando-as às diferentes faixas etárias.info:eu-repo/semantics/publishedVersio

Accumulation of northern krill (Meganyctiphanes norvegica) in a convergence zone at the Cap Breton Canyon (southern Bay of Biscay)

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