Role of membrane curvature on the activation/deactivation of Carnitine Palmitoyltransferase 1A: A coarse grain molecular dynamic study

Carnitine Palmitoyltransferase 1A (CPT 1A) is an enzyme anchored to the outer mitochondrial membrane (OMM), where it regulates the passage of fatty acids into the mitochondria and intervenes in the process of β-oxidation of long-chain fatty acids. Although CPT 1A is inhibited by malonyl-CoA, its activity is also modulated by the curvature of OMM. This modulation depends on the behavior of the N-terminal domain (NTD), which can be adsorbed onto the OMM (nonactive CPT 1A) or interacting with the C-terminal domain (active CPT 1A). Aimed to provide mechanistic insights on the regulatory mechanism of CPT 1A, we studied the influence of the bilayer curvature on the NTD behavior through a series of coarse-grained (CG) molecular dynamics simulations using curved and planar membranes. Comparative analysis suggests that the main determinant for the activation/deactivation of the enzyme is the tilt angle orientation of the transmembrane (TM) domains. Planar membranes induce a wide variation on the tilt angle orientation of TM helices, while curved geometries promote small angles with the membrane normal. Our results identify the first TM domain as an important component of the membrane sensing mechanism.Fil: Frigini, Ezequiel Nazareno. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Barrera, Exequiel E.. Instituto Pasteur de Montevideo; UruguayFil: Pantano, Sergio. Instituto Pasteur de Montevideo; UruguayFil: Porasso, Rodolfo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; Argentin

A homogeneous dataset of polyglutamine and glutamine rich aggregating peptides simulations

This dataset contains a collection of molecular dynamics (MD) simulations of polyglutamine (polyQ) and glutamine-rich (Q-rich) peptides in the multi-microsecond timescale. Primary data from coarse-grained simulations performed using the SIRAH force field has been processed to provide fully atomistic coordinates. The dataset encloses MD trajectories of polyQs of 4 (Q4), 11 (Q11), and 36 (Q36) amino acids long. In the case of Q11, simulations in presence of Q5 and QEQQQ peptides, which modulate aggregation, are also included. The dataset also comprises MD trajectories of the gliadin related p31-43 peptide, and Insulin's C-peptide at pH=7 and pH=3.2, which constitute examples of Q-rich and Q-poor aggregating peptides. The dataset grants molecular insights on the role of glutamines in spontaneous and unbiased ab-initio aggregation of a series of peptides using a homogeneous set of simulations [1]. The trajectory files are provided in Protein Data Bank (PDB) format containing the Cartesian coordinates of all heavy atoms in the aggregating peptides. Further analyses of the trajectories can be performed directly using any molecular visualization/analysis software suites

Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer

A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ42 aggregates. The early stage interaction between compound 7 and the Aβ42 monomer was investigated by replica exchange molecular dynamics (REMD) simulations and docking studies. Our theoretical results revealed that compound 7 can elongate the helical conformation state of an early stage Aβ42 monomer and it helps preventing the formation of β-sheet structures by interacting with key residues in the central hydrophobic cluster (CHC). This strategy where early “on-pathway” events are monitored by small molecules will help the development of new therapeutic strategies for Alzheimer’s disease

Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior

Apolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport mediated by the high-density lipoprotein (HDL) particles. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural impacts introduced by these mutations, there is little information addressing the relationship between the evolutionary and structural features that contribute to the amyloid behavior of apoA-I. We combined evolutionary studies, in silico saturation mutagenesis and molecular dynamics (MD) simulations to provide a comprehensive analysis of the conservation and pathogenic role of the aggregation-prone regions (APRs) present in apoA-I. Sequence analysis demonstrated the pervasive conservation of an APR, designated here APR1, within the N-terminal ɑ-helix bundle. Moreover, stability analysis carried out with the FoldX engine showed that this motif contributes to the marginal stability of apoA-I. Structural properties of the full-length apoA-I model suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its structure. Compared to HDL-deficiency or natural silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of apoA-I point mutations associated with amyloid pathologies were found to show a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the ɑ-helix bundle and the occurrence of β-strand secondary elements at the C-terminus of apoA-I. Our findings highlight APR1 as a relevant component for apoA-I structural integrity and emphasize a destabilizing effect of amyloid variants that leads to the exposure of APRs. This information contributes to our understanding of how apoA-I, with its high degree of structural flexibility, maintains a delicate equilibrium between its native structure and intrinsic tendency to form amyloid aggregates. In addition, our stability measurements could be used as a proxy to interpret the structural impact of new mutations affecting apoA-I.Instituto de Investigaciones Bioquímicas de La PlataInstituto de Biotecnologia y Biologia Molecula

10 MeV proton irradiation effects on GaInP/GaAs/Ge concentrator solar cells and their component subcells

In this paper, the experimental results of a 10 MeV proton irradiation on concentrator GaInP/GaAs/Ge lattice-matched triple-junction solar cells and their corresponding subcells are examined. Electro-optical characterization such as external quantum efficiency, light and dark I-V measurements, is performed together with theoretical device modeling in order to guide the analysis of the degradation behavior. The GaInP (on Ge) and Ge cell showed a power loss between beginning of life and end of life of about 4% while the GaInP/GaAs/Ge and GaAs solar cells exhibited the highest damage measured of 12% and 10%, respectively for an irradiation fluence equivalent to an 8-years satellite mission in Low Earth Orbit. The results from single-junction solar cells correlate well with those of triple-junction solar cells. The performance of concentrator solar cells structures is similar to that of traditional space-targeted designs reported in literature suggesting that no special changes may be required to use triple junction concentrator solar cells in space.Fil: Ochoa, M.. Universidad Politécnica de Madrid; EspañaFil: Yaccuzzi, Exequiel Eliseo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Espinet González, P.. Universidad Politécnica de Madrid; EspañaFil: Barrera, Marcela Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Barrigón, E.. Universidad Politécnica de Madrid; EspañaFil: Ibarra, María Luján. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Contreras, Yedileth. Universidad Politécnica de Madrid; EspañaFil: Garcia, Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: López, E.. Universidad Politécnica de Madrid; EspañaFil: Alurralde, M.. Comisión Nacional de Energía Atómica; ArgentinaFil: Algora, C.. Universidad Politécnica de Madrid; EspañaFil: Godfrin, E.. Comisión Nacional de Energía Atómica; ArgentinaFil: Rey Stolle, I.. Universidad Politécnica de Madrid; EspañaFil: Plá, J.. Comisión Nacional de Energía Atómica; Argentina. Universidad Nacional de San Martín; Argentin

Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer

A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ42 aggregates. The early stage interaction between compound 7 and the Aβ42 monomer was investigated by replica exchange molecular dynamics (REMD) simulations and docking studies. Our theoretical results revealed that compound 7 can elongate the helical conformation state of an early stage Aβ42 monomer and it helps preventing the formation of β-sheet structures by interacting with key residues in the central hydrophobic cluster (CHC). This strategy where early “on-pathway” events are monitored by small molecules will help the development of new therapeutic strategies for Alzheimer’s disease