Molecular dynamics modelling of skin and hair proteins

The binding free energy is one of the most important and desired thermodynamic properties in simulations of biological systems. The propensity of small molecules binding to macromolecules of human bio-substrates regulates their sub-cellular disposition. This subject is fundamental in transdermal permeation and hair absorption of cosmetic actives. Biomechanical and biophysical properties of hair and skin are related to keratin as their major constituent. A key challenge lies in predicting molecular and thermodynamic basis as the result of small molecules interacting with alpha helical keratin at the molecular level. In addition, elastic properties of human skin which are directly related to the interactions of keratin intermediate filaments remain a challenging subject. Molecular dynamics (MD) simulations provide a possibility of observing biological processes within atomistic resolution providing more detailed insight into experimental results. However, MD simulations are limited in terms of the achievable time scales. Hence, in this thesis MD simulations were employed in order to provide better understanding of the experimental results conducted in parallel and to overcome the main limiting factor of MD – the simulation time. For this purpose, thermodynamic and detailed structural basis have been delivered for small molecules interacting with keratin explaining and validating experimental data. On the top of this the fast free energy prediction tool has been built within all-atom force field by a use of steered molecular dynamics alone. Within the coarse grain approach, the force field was developed for the application of elastic properties of human skin enabling orders of magnitude faster than all-atom force fields simulations. The application of the coarser representation enabled assessing the influence of the natural moisturizing factor composed of small molecules on the elastic properties of the outermost human skin layer. In this work, MD results reached excellent agreement with the experimental data.Open Acces

Bridging the N-terminal and middle domains in FliG of the flagellar rotor

Flagella are necessary for bacterial movement and contribute to various aspects of virulence. They are complex cylindrical structures built of multiple molecular rings with self-assembly properties. The flagellar rotor is composed of the MS-ring and the C-ring. The FliG protein of the C-ring is central to flagellar assembly and function due to its roles in linking the C-ring with the MS-ring and in torque transmission from stator to rotor. No high-resolution structure of an assembled C-ring has been resolved to date, and the conformation adopted by FliG within the ring is unclear due to variations in available crystallographic data. Here, we use molecular dynamics (MD) simulations to study the conformation and dynamics of FliG in different states of assembly, including both in physiologically relevant and crystallographic lattice environments. We conclude that the linker between the FliG N-terminal and middle domain likely adopts an extended helical conformation in vivo, in contrast with the contracted conformation observed in some previous X-ray studies. We further support our findings with integrative model building of full-length FliG and a FliG ring model that is compatible with cryo-electron tomography (cryo-ET) and electron microscopy (EM) densities of the C-ring. Collectively, our study contributes to a better mechanistic understanding of the flagellar rotor assembly and its function

Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity

Biomolecular simulation is increasingly central to understanding and designing biological molecules and their interactions. Detailed, physics‐based simulation methods are demonstrating rapidly growing impact in areas as diverse as biocatalysis, drug delivery, biomaterials, biotechnology, and drug design. Simulations offer the potential of uniquely detailed, atomic‐level insight into mechanisms, dynamics, and processes, as well as increasingly accurate predictions of molecular properties. Simulations can now be used as computational assays of biological activity, for example, in predictions of drug resistance. Methodological and algorithmic developments, combined with advances in computational hardware, are transforming the scope and range of calculations. Different types of methods are required for different types of problem. Accurate methods and extensive simulations promise quantitative comparison with experiments across biochemistry. Atomistic simulations can now access experimentally relevant timescales for large systems, leading to a fertile interplay of experiment and theory and offering unprecedented opportunities for validating and developing models. Coarse‐grained methods allow studies on larger length‐ and timescales, and theoretical developments are bringing electronic structure calculations into new regimes. Multiscale methods are another key focus for development, combining different levels of theory to increase accuracy, aiming to connect chemical and molecular changes to macroscopic observables. In this review, we outline biomolecular simulation methods and highlight examples of its application to investigate questions in biology. This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Free Energy Method

Fruit ontogenesis in Clusia parviflora Humb. & Bonpl. ex Willd. (Clusiaceae) Ontogênese do fruto de Clusia parviflora Humb. & Bonpl. ex Willd. (Clusiaceae)

Aspects of the morpho-anatomy of developing fruits and seeds of Clusia parviflora are presented and discussed as a continuation of the study of these organs in Clusiaceae. The fruit is a septifrage capsule; the suberized exocarp is derived from the external epidermis of the ovary. The mesocarp originates from the ovarian mesophyll and remains parenchymal in nature. The endocarp is derived from the internal epidermis of the ovary and the endocarp is derived from the inner ovary epidermis as well as from three to four adjacent subepidermal layers, with tangentially elongated cells which become lignified and contribute to fruit dehiscence. The ovules are anatropous, bitegmic, with an endothelium, and give rise to equally anatropous seeds. The exotesta has cells containing phenolic compounds. The exotegmen consists entirely of sclerids with anticlinal and undulating cell walls, while the rest of the tegmen collapses during maturation. The embryo is slightly curved and the hypocotyl-radicle axis is well developed, with two very small cotyledons. There seems to be uniformity in the genus Clusia as regards the final number of layers in the mature seed coat, being evident the continuous lignified exotegmen and the hypocotylar embryo. It should be pointed out that the number of layers in the ovule integument can be used for diagnosis at the species levelAspectos morfo-anatômicos dos frutos e sementes em desenvolvimento de Clusia parviflora são apresentados e discutidos, visando dar continuidade aos estudos com estes órgãos em Clusiaceae. O fruto é cápsula septífraga; o exocarpo suberificado deriva da epiderme externa do ovário. O mesocarpo, originado do mesofilo ovariano, permanece parenquimático. O endocarpo é derivado da epiderme interna do ovário e de três a quatro camadas subepidérmicas, cujas células tangencialmente alongadas tornam-se lignificadas, contribuindo para a deiscência do fruto. Os óvulos são anátropos, bitegumentados, com endotélio, e originam sementes também anátropas, bitegumentadas e exalbuminosas. A exotesta apresenta células de conteúdo fenólico. O exotégmen consta inteiramente de esclereídes com paredes anticlinais onduladas. O restante do tégmen torna-se colapsado. O embrião é levemente curvado e apresenta um eixo hipocótilo-radicular cilíndrico e muito desenvolvido, com dois cotilédones muito pequenos. Parece haver uniformidade em Clusiacom relação ao número de camadas no tegumento seminal maduro, mas o número de camadas no tegumento ovulífero pode ser um caráter diagnóstico em nível específico

A motivação de adolescentes nas aulas de Educação Física

O objetivo deste estudo, originalmente parte de dissertação de mestrado homônima desenvolvida no Programa de Pós-Graduação em Educação Física da Universidade Católica de Brasília, foi verificar se existem diferenças motivacionais intrínsecas e extrínsecas entre os sexos masculino e feminino das 8as séries do ensino fundamental e 3as séries do ensino médio para a prática das aulas de Educação Física. Esta pesquisa caracterizou-se como sendo descritiva. A amostra foi composta de 279 alunos de ambos os sexos, na faixa etária de 14 a 17 anos, de 8as séries do ensino fundamental e 3as séries do ensino médio do colégio Branca da Mota Fernandes do município de Maringá-PR, que se dispuseram a participar da pesquisa. O instrumento de coleta de dados utilizado foi elaborado por KOBAL (1996); trata-se de um questionário referente à identificação de motivos intrínsecos e extrínsecos. Na análise de dados foram verificadas as médias e percentuais (análise quantitativa) através do Teste-t para amostras independentes. Diante das diferenças verificadas entre os sexos masculino e feminino, pode-se considerar que os alunos de oitavas séries do ensino fundamental estão mais motivados que os de terceiras séries do ensino médio para a prática das aulas de Educação Física

The nanotube express: delivering a stapled peptide to the cell surface

Research Dat

The structural basis for membrane assembly of immunoreceptor signalling complexes

Immunoreceptors are TM complexes that consist of separate ligand-binding and signal-transducing modules. Mounting evidence suggests that interactions with the local environment may influence the architecture of these TM domains, which assemble via crucial sets of conserved ionisable residues, and also control the peripheral association of immunoreceptor tyrosine-based activation motifs (ITAMs) whose phosphorylation triggers cytoplasmic signalling cascades. We now report a molecular dynamics (MD) simulation study of the archetypal T cell receptor (TCR) and its cluster of differentiation 3 (CD3) signalling partners, along with the analogous DNAX-activation protein of 12 kDa (DAP12)/natural killer group 2C (NKG2C) complex. Based on > 15 μs of explicitly solvated, atomic-resolution sampling, we explore molecular aspects of immunoreceptor complex stability in different functionally relevant states. A novel alchemical approach is used to simulate the cytoplasmic CD3ε tail at different depths within lipid bilayer models, revealing that the conformation and cytoplasmic exposure of ITAMs are highly sensitive to local enrichment by different lipid species and to phosphorylation. Furthermore, simulations of the TCR and DAP12 TM domains in various states of oligomerisation suggest that, during the early stages of assembly, stable membrane insertion is facilitated by the interfacial lipid/solvent environment and/or partial ionisation of charged residues. Collectively, our results indicate that the architecture and mechanisms of signal transduction in immunoreceptor complexes are tightly regulated by interactions with the microenvironment