ABSTRACT
Charge scaling has proven to be an efficient way to account in a mean-field manner for electronic polarization by aqueous ions in force field molecular dynamics simulations. However, commonly used water models with dielectric constants over 50 are not consistent with this approach leading to "overscaling", i.e., generally too weak ion-ion interactions. Here, we build water models fully compatible with charge scaling, i.e., having the correct low-frequency dielectric constant of about 45. To this end, we employ advanced optimization and machine learning schemes in order to explore the vast parameter space of four-site water models efficiently. As an a priori unwarranted positive result, we find a sizable range of force field parameters that satisfy the above dielectric constant constraint providing at the same time accuracy with respect to experimental data comparable with the best existing four-site water models such as TIP4P/2005, TIP4P-FB, or OPC. The present results thus open the way to the development of a consistent charge scaling force field for modeling ions in aqueous solutions.
ABSTRACT
The functional properties of some biological ion channels and membrane transport proteins are proposed to exploit anion-hydrophobic interactions. Here, we investigate a chloride-pumping rhodopsin as an example of a membrane protein known to contain a defined anion binding site composed predominantly of hydrophobic residues. Using molecular dynamics simulations, we explore Cl- binding to this hydrophobic site and compare the dynamics arising when electronic polarization is neglected (CHARMM36 [c36] fixed-charge force field), included implicitly (via the prosECCo force field), or included explicitly (through the polarizable force field, AMOEBA). Free energy landscapes of Cl- moving out of the binding site and into bulk solution demonstrate that the inclusion of polarization results in stronger ion binding and a second metastable binding site in chloride-pumping rhodopsin. Simulations focused on this hydrophobic binding site also indicate longer binding durations and closer ion proximity when polarization is included. Furthermore, simulations reveal that Cl- within this binding site interacts with an adjacent loop to facilitate rebinding events that are not observed when polarization is neglected. These results demonstrate how the inclusion of polarization can influence the behavior of anions within protein binding sites and can yield results comparable with more accurate and computationally demanding methods.
Subject(s)
Chlorides , Rhodopsin , Chlorides/chemistry , Anions , Molecular Dynamics Simulation , ElectronicsABSTRACT
Light and heavy water are often used interchangeably in spectroscopic experiments with the tacit assumption that the structure of the investigated biomolecule does not depend too much on employing one or the other solvent. While this may often be a good approximation, we demonstrate here using molecular dynamics simulations incorporating nuclear quantum effects via modification of the interaction potential that there are small but significant differences. Namely, as quantified and discussed in the present study, both proteins and biomembranes tend to be slightly more compact and rigid in D2O than in H2O, which reflects the stronger hydrogen bonding in the former solvent.
Subject(s)
Proteins , Water , Water/chemistry , Deuterium Oxide/chemistry , Thermodynamics , Solvents/chemistryABSTRACT
Small differences in physical and chemical properties of H2O and D2O, such as melting and boiling points or pKa, can be traced back to a slightly stronger hydrogen bonding in heavy versus normal water. In particular, deuteration reduces zero-point vibrational energies as a demonstration of nuclear quantum effects. In principle, computationally demanding quantum molecular dynamics is required to model such effects. However, as already demonstrated by Feynmann and Hibbs, zero-point vibrations can be effectively accounted for by modifying the interaction potential within classical dynamics. In the spirit of the Feymann-Hibbs approach, we develop here two water models for classical molecular dynamics by fitting experimental differences between H2O and D2O. We show that a three-site SPCE-based model accurately reproduces differences between properties of the two water isotopes, with a four-site TIP4P-2005/based model in addition capturing also the absolute values of key properties of heavy water. The present models are computationally simple enough to allow for extensive simulations of biomolecules in heavy water relevant, for example, for experimental techniques such as NMR or neutron scattering.
ABSTRACT
Hydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively demonstrate that humans are, nevertheless, able to distinguish D2O from H2O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and can add to perceived sweetness of sweeteners. In contrast, mice do not prefer D2O over H2O, indicating that they are not likely to perceive heavy water as sweet. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and chimeric G-proteins are activated by D2O but not by H2O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D2O in human sensory tests, as well as the calcium release elicited by D2O in sweet taste receptor-expressing cells. The present multifaceted experimental study, complemented by homology modelling and molecular dynamics simulations, resolves a long-standing controversy about the taste of heavy water, shows that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of the detailed mechanism of action.
Subject(s)
Deuterium Oxide/analysis , Mice, Inbred C57BL/physiology , Receptors, G-Protein-Coupled/metabolism , Taste Perception , Taste , Adult , Animals , Cell Line , Female , Humans , Male , Mice , Molecular Dynamics Simulation , Transfection , Young AdultABSTRACT
Resumen: Introducción: en los últimos diez años las investigaciones en el área de salud sexual y reproductiva (SSyR) en la adolescencia se han enfocado sobre todo en la mujer. Se requieren estudios que centren su investigación en el varón con el fin de generar espacios de calidad destinados al abordaje de prevención y promoción de SSyR en varones. Objetivo: conocer las prácticas, actitudes y conocimientos en SSyR en varones adolescentes usuarios de la Unidad Docente Asistencial (UDA) Canelones al Este. Conocer las fuentes que utilizan para recabar información y aclarar sus inquietudes en relación con diferentes situaciones planteadas. Material y método: estudio observacional descriptivo de tipo encuesta autoadministrada. Período: julio-agosto 2018. Criterios de inclusión: adolescentes varones usuarios de la Administración de los Servicios de Salud del Estado (ASSE) que concurrieron a control en las policlínicas de UDA Canelones al Este. Fuente de datos: encuesta. Análisis de datos: frecuencias absolutas y relativas para variables cualitativas. Programa PSPP Statistics 1.0.1 (2018). Resultados: se incluyeron 60 adolescentes varones. La media de edad fue de 15 años; 37 iniciaron sus relaciones sexuales (67,5%) antes de los 15 años. Las principales fuentes de información sobre sexualidad y pubertad fueron familia 35%, amigos 20%. El 56,7% conocía las enfermedades de transmisión sexual. Dentro de los métodos anticonceptivos más conocidos y utilizados se destaca el preservativo masculino, 86,7%. El 30% de los adolescentes utilizaban preservativo durante las relaciones sexuales. Conclusiones: los resultados que se presentan en esta investigación muestran algunos aspectos de la SSyR de los varones adolescentes. Ello permitirá generar medidas para abordar e integrar más al varón adolescente en el sistema de salud y así disminuir la brecha que existe hoy día con esta población.
Summary: Introduction: in the last 10 years, adolescent sexual and reproductive health (SRH) research has mainly focused on women. Male adolescent studies are necessary in order to promote SRH in this population. Objective: determine the SRH male adolescent understanding, attitudes and practices for users of UDA Canelones al Este. Learn about the information sources they use to address their concerns in this matter. Method: cross-sectional descriptive observational survey. Period: July-August 2018. Inclusion criteria: male adolescent users of ASSE who attended a health check-up at the UDA Canelones al Este Clinic. Data source: survey. data analysis: Absolute and relative frequencies for qualitative variables. PSPP Statistics 1.0.1 Program (2018). Results: sixty male adolescents were included in the study. The average age was 15 years of age. They started to have sexual intercourse n = 37; 67.5% before the age of 15. The main sources of information on sexuality and puberty came 35% from relatives and 20% from friends. 56.7% knew about sexually transmitted diseases. Among the best known and most used contraceptive methods was the male condom with 86.7%. 30% of adolescents always used contraceptive methods during intercourse. Conclusions: the results presented in this research show some aspects of male adolescent sexual and reproductive health. They will enable us to devise measures to address and integrate more adolescent males in the health system and thus reduce the presently existing gap with this population.
Resumo: Introdução: nos últimos 10 anos, as pesquisas sobre saúde sexual e reprodutiva (SSR) de adolescentes focalizaram-se principalmente nas mulheres, mas estudos com adolescentes do sexo masculino são necessários para promover a SSR nessa população. Objetivo: determinar o nível de conhecimento, atitudes e práticas em SSR dos adolescentes do sexo masculino usuários de UDA Canelones al Este. Conhecer mais sobre as fontes de informação que eles usaram para responder suas preocupações neste assunto. Método: pesquisa observacional descritiva transversal. Período: julho a agosto de 2018. Critérios de inclusão: adolescentes do sexo masculino usuários da ASSE que realizaram controles na clínica UDA Canelones al Este. Fonte de dados: Pesquisa. Análise de dados: Frequências absolutas e relativas para variáveis qualitativas. Programa PSPP Statistics 1.0.1 (2018). Resultados: sessenta adolescentes do sexo masculino foram incluídos no estudo. A idade média foi de 15 anos. Eles começaram a ter relações sexuais n = 37; 67,5% antes dos 15 anos. As principais fontes de informação sobre sexualidade e puberdade vieram 35% de familiares e 20% de amigos. 56,7% sabiam sobre doenças sexualmente transmissíveis. Dentre os métodos anticoncepcionais mais conhecidos e mais utilizados esteve o preservativo masculino com 86,7%. 30% dos adolescentes sempre usaram métodos anticoncepcionais durante a relação sexual. Conclusões: os resultados apresentados nesta pesquisa mostram alguns aspectos da saúde sexual e reprodutiva dos homens adolescentes. Eles nos permitirão desenhar medidas para abordar e integrar mais aos adolescentes do sexo masculino no sistema de saúde e, assim, reduzir a brecha atualmente existente com essa população.
