Dimensionality of Carbon Nanomaterials Determines the Binding and Dynamics of Amyloidogenic Peptides: Multiscale Theoretical Simulations

Experimental studies have demonstrated that nanoparticles can affect the rate of protein self-assembly, possibly interfering with the development of protein misfolding diseases such as Alzheimer's, Parkinson's and prion disease caused by aggregation and fibril formation of amyloid-prone proteins. We employ classical molecular dynamics simulations and large-scale density functional theory calculations to investigate the effects of nanomaterials on the structure, dynamics and binding of an amyloidogenic peptide apoC-II(60-70). We show that the binding affinity of this peptide to carbonaceous nanomaterials such as C60, nanotubes and graphene decreases with increasing nanoparticle curvature. Strong binding is facilitated by the large contact area available for π-stacking between the aromatic residues of the peptide and the extended surfaces of graphene and the nanotube. The highly curved fullerene surface exhibits reduced efficiency for π-stacking but promotes increased peptide dynamics. We postulate that the increase in conformational dynamics of the amyloid peptide can be unfavorable for the formation of fibril competent structures. In contrast, extended fibril forming peptide conformations are promoted by the nanotube and graphene surfaces which can provide a template for fibril-growth

Introdução à edição especial: pessoas refugiadas ou deslocadas no ambiente de trabalho

This special issue focuses on refugees’ experiences and displaced people across a diverse set of ethnicities and circumstances. The growing number of refugees and displaced people and the work and life difficulties they face are central social issues in the world today. This special issue will explore how refugees and displaced people in Brazil can be fully integrated, socialized, engaged, embraced, and affirmed into the workplace and society. Research is presented on the experiences of refugees and displaced people, a growing but under-researched segment of the world’s population. Little is known about refugees’ career experiences and displaced people and how organizations, leaders, and policymakers can assist them in finding work, maintaining employment, and creating positive life outcomes. There are 12 articles included in this special issue. They focus on three areas of refugees in the workplace. The first area explores biases in the perceptions of refugees based on factors such as skin complexion, countries of origin, and race. The second area presents research that elaborates on the theme of displacement of refugees and barriers to integration, inclusion, social recognition, and belonging. The third area examines ways in which refugees have been integrated and acculturated into Brazilian society, often through the assistance of NGOs or through the efforts of managers in the workplace. It is our hope that the research presented in this special issue will increase interest in this important topic and lead to additional future research related to reducing barriers to integration and acculturation that refugees and displaced people face.Esta edición especial se centra en las experiencias de los refugiados y desplazados en medio de un conjunto diverso de etnias y circunstancias. El creciente número de personas en estas condiciones, así como sus dificultades en la vida y en el trabajo, son cuestiones sociales centrales en el mundo actual. Los estudios publicados en esta edición exploran cómo los refugiados y las personas desplazadas –una población aún poco estudiada, pero que crece en todo el planeta – pueden ser plenamente integrados, socializados, involucrados, acogidos y afianzados en el lugar de trabajo y en la sociedad, considerando el contexto brasileño. Poco se sabe sobre las experiencias profesionales de esta población y sobre cómo organizaciones, líderes y formuladores de políticas públicas pueden contribuir a que esta encuentre trabajo, mantenga su empleo y logre buenos resultados en la vida. Aquí se presentan 12 artículos reunidos en tres áreas relacionadas con el tema de los refugiados y su lugar de trabajo. La primera área explora los prejuicios en las percepciones con respecto a los refugiados en función de factores como el tono de piel, el país de origen y la raza. La segunda presenta investigaciones que abordan el desplazamiento de refugiados y las barreras a la integración, inclusión, reconocimiento social y pertenencia. Finalmente, la tercera área examina cómo los refugiados han sido integrados y aculturados en la sociedad brasileña, a menudo a través de la asistencia de organizaciones de la sociedad civil o mediante los esfuerzos de gestores en el lugar de trabajo. Esperamos que las investigaciones presentadas en esta edición especial contribuyan a incrementar el interés en este importante tema e inspiren futuros estudios que puedan conducir a la reducción de las barreras que enfrentan los refugiados y desplazados en sus procesos de integración y aculturación.Esta edição especial se concentra nas experiências de refugiados e deslocados em meio a um conjunto diversificado de etnias e circunstâncias. O número crescente de pessoas nessas condições, bem como suas dificuldades na vida e no trabalho, são questões sociais centrais no mundo de hoje. A presente edição traz estudos que exploram como refugiados e deslocados – uma população ainda pouco estudada, mas crescente em todo o planeta – podem ser totalmente integrados, socializados, engajados, acolhidos e afirmados no local de trabalho e na sociedade, considerando o contexto brasileiro. Pouco se sabe sobre as experiências de carreira dessa população e sobre como organizações, lideranças e formuladores de políticas públicas podem contribuir para que ela possa encontrar trabalho, manter empregos e alcançar bons resultados na vida. São apresentados aqui 12 artigos, reunidos em três áreas relacionadas ao tema dos refugiados e seu local de trabalho. A primeira área explora preconceitos nas percepções a respeito de pessoas refugiadas em base a fatores como o tom da pele, país de origem e raça. A segunda apresenta pesquisas que abordam o deslocamento de refugiados e as barreiras à integração, inclusão, reconhecimento social e pertencimento. A terceira área, finalmente, examina com os refugiados têm sido integrados e aculturados na sociedade brasileira, muitas vezes por meio da assistência de organizações da sociedade civil ou pelos esforços de gestores no local de trabalho. Esperamos que as pesquisas apresentadas nesta edição especial contribuam para ampliar o interesse nesse importante tópico, inspirando futuros estudos que possam levar à redução das barreiras enfrentadas pelos refugiados e deslocados em seus processos de integração e aculturação

Intro to This Special Issue: Refugees/Displaced People in the Workplace

This special issue focuses on refugees’ experiences and displaced people across a diverse set of ethnicities and circumstances. The growing number of refugees and displaced people and the work and life difficulties they face are central social issues in the world today. This special issue will explore how refugees and displaced people in Brazil can be fully integrated, socialized, engaged, embraced, and affirmed into the workplace and society. Research is presented on the experiences of refugees and displaced people, a growing but under-researched segment of the world’s population. Little is known about refugees’ career experiences and displaced people and how organizations, leaders, and policymakers can assist them in finding work, maintaining employment, and creating positive life outcomes. There are 12 articles included in this special issue. They focus on three areas of refugees in the workplace. The first area explores biases in the perceptions of refugees based on factors such as skin complexion, countries of origin, and race. The second area presents research that elaborates on the theme of displacement of refugees and barriers to integration, inclusion, social recognition, and belonging. The third area examines ways in which refugees have been integrated and acculturated into Brazilian society, often through the assistance of NGOs or through the efforts of managers in the workplace. It is our hope that the research presented in this special issue will increase interest in this important topic and lead to additional future research related to reducing barriers to integration and acculturation that refugees and displaced people face

APOA2 increases cholesterol efflux capacity to plasma HDL by displacing the C-terminus of resident APOA1

Abstract The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity. APOA2 likewise increased the cholesterol efflux capacity of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up experiments with reconstituted HDL corroborated that the presence of both APOA1 and APOA2 were necessary for the increased efflux. Using limited proteolysis and chemical cross-linking mass spectrometry, we found that APOA2 induced a conformational change in the N- and C-terminal helices of APOA1. Using reconstituted HDL with APOA1 deletion mutants, we further showed that APOA2 lost its ability to stimulate ABCA1 efflux to HDL if the C-terminal domain of APOA1 was absent, but retained this ability when the N-terminal domain was absent. Based on these findings, we propose a model in which APOA2 displaces the C-terminal helix of APOA1 from the HDL surface which can then interact with ABCA1—much like it does in lipid-poor APOA1. These findings suggest APOA2 may be a novel therapeutic target given this ability to open a large, high-capacity pool of HDL particles to enhance ABCA1-mediated cholesterol efflux

Flipped C-Terminal Ends of apoA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs

Background: Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear. Methods: We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of apoA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs. Results: We quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometry analysis of chemically cross-linked peptides and molecular dynamics simulations of apoA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, the small HDLs (eg, reconstituted HDLs) of which are discoidal and composed of apoA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC. Conclusions: We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of apoA1 are "flipped" off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL

Folding of the apolipoprotein A1 driven by the salt concentration as a possible mechanism to improve cholesterol trapping

The folding of the cholesterol trapping apolipoprotein A1 in aqueous solution at increasing ionic strength is studied using atomically detailed molecular dynamics simulations. We calculate various structural properties to characterize the conformation of the protein, such as the radius of gyration, the radial distribution function and the end to end distance. Additionally we report information using tools specifically tailored for the characterization of proteins, such as the mean smallest distance matrix and the Ramachandran plot. We find that two qualitatively different configurations of this protein are preferred, one where the protein is extended, and one where it forms loops or closed structures. It is argued that the latter promote the association of the protein with cholesterol and other fatty acids.Comment: 14 pages, 6 figures. To appear in "Selected Topics of Computational and Experimental Fluid Mechanics", Springer, J. Klapp, G. Ru\'iz, A. Medina, A. L\'opez & L. Di G. Sigalotti (eds.), 201

Role of Lipids in Spheroidal High Density Lipoproteins

We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules surrounding the lipid compartment. The present models are the first ones among computational studies where the size and lipid composition of HDL are realistic, corresponding to human serum HDL. We focus on the role of lipids in HDL structure and dynamics. Particular attention is paid to the assembly of lipids and the influence of lipid-protein interactions on HDL properties. We find that the properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). Unlike the hydrophobic core, the intermediate and surface regions are characterized by prominent conformational lipid order. Yet, not only the conformations but also the dynamics of lipids are found to be distinctly different in the different regions of HDL, highlighting the importance of dynamics in considering the functionalization of HDL. The structure of the lipid droplet close to the HDL-water interface is altered by the presence of apoA-Is, with most prominent changes being observed for cholesterol and polar lipids. For cholesterol, slow trafficking between the surface layer and the regimes underneath is observed. The lipid-protein interactions are strongest for cholesterol, in particular its interaction with hydrophobic residues of apoA-I. Our results reveal that not only hydrophobicity but also conformational entropy of the molecules are the driving forces in the formation of HDL structure. The results provide the first detailed structural model for HDL and its dynamics with and without apoA-I, and indicate how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly

Disclosure of cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor

Cholesterol influences ion-channel function, distribution and clustering in the membrane, endocytosis, and exocytic sorting of the nicotinic acetylcholine receptor (AChR). We report the occurrence of a cholesterol recognition motif, here coined “CARC”, in the transmembrane regions of AChR subunits that bear extensive contact with the surrounding lipid, and are thus optimally suited to convey cholesterol-mediated signaling from the latter. Three cholesterol molecules could be docked on the transmembrane segments of each AChR subunit, rendering a total of 15 cholesterol molecules per AChR molecule. The CARC motifs contribute each with an energy of interaction between 35 and 52 kJ.mol−1, adding up to a total of about 200 kJ.mol−1 per receptor molecule, i.e. ∼40% of the lipid solvation free energy/ AChR molecule. The CARC motif is remarkably conserved along the phylogenetic scale, from prokaryotes to human, suggesting that it could be responsible for some of the above structural/functional properties of the AChR