12 research outputs found
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
Interaction of glycine, lysine, proline and histidine with dipalmitoylphosphatidylcholine lipid bilayers: a theoretical and experimental study
The interaction of unblocked glycine, lysine, proline, and histidine (in their three forms, namely two tautomers and the protonated form) with a dipalmitoylphosphatidylcholine (DPPC) bilayer was assessed using extensive atomistic molecular dynamics simulations. Free energy profiles for the insertion of each amino acid into the lipid bilayer were computed along an appropriated reaction coordinate. The simulation results for glycine in the presence of DPPC were compared with experimental data obtained by Fourier transform infrared spectroscopy. Experimental results predict, in good agreement with simulations, the existence of intermolecular interactions between the DPPC head groups and glycine. Atomistic simulations were further extended to investigate the free energy profiles for lysine, proline and histidine, leading to the following conclusions: (i) lysine free energy profiles computed using a united atom force-field and an analog molecule, where the side-chain is truncated at the β-carbon atom, differ significantly from each other; (ii) the free energy profiles for the three forms of histidine are all very similar, although the charged form interacts mostly with the carbonyl groups of DPPC, while the tautomers interact with the phosphate groups; and (iii) proline does not show a minimum in the free energy profile, pointing to the absence of binding to the membrane lipids. Overall, this work contributes to our general understanding of the various factors affecting the interactions between amino acids and a model cell membrane, and may spur progress in the effort to develop new molecular models to study larger biological systems.Fil: Porasso, Rodolfo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; ArgentinaFil: Ale, Norma Mercedes. Universidad Nacional de Tucuman. Facultad de Bioquimica, Quimica y Farmacia. Instituto de Quimica Fisica; ArgentinaFil: Ciocco Aloia, Facundo. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Masone, Diego Fernando. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: del Popolo, Mario Gabriel. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ben Altabef, Aida. Universidad Nacional de Tucuman. Facultad de Bioquimica, Quimica y Farmacia. Instituto de Quimica Fisica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto de Quimica del Noroeste; ArgentinaFil: Gomez Zavaglia, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Investigaciones en Criotecnología de Alimentos (i); ArgentinaFil: Díaz, Sonia Beatriz. Universidad Nacional de Tucuman. Facultad de Bioquimica, Quimica y Farmacia. Instituto de Quimica Fisica; ArgentinaFil: Vila, Jorge Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; Argentina. Cornell University; Estados Unido
Study of the effect of Na+ and Ca2+ ion concentration on the structure of an asymmetric DPPC/DPPC+DPPS lipid bilayer by Molecular Dynamics Simulation
A Molecular Dynamics Simulation study of the steady and dynamic properties of an asymmetric phospholipid bilayer was carried out in the presence of sodium or calcium ions. The asymmetric lipid bilayer was seen to resemble a cellular membrane of an eukaryotic cell, which was modeled by DiPalmitoylPhosphatidylCholine (DPPC) and DiPalmitoylPhosphatidylSerine (DPPS), placing the DPPS in one of the two leaflets of the lipid bilayer.From a numerical analysis of the simulated trajectories, information was obtained with atomic resolution for both membrane leaflet concerning the effect of bilayer asymmetry on different properties of the lipid/water interface, such as the translational diffusion coefficient and rotational relaxation time of the water molecules, lipid hydration, and residence time of water around different lipid atoms. In addition, information related to lipid conformation, and lipid-lipid interactions was also analyzed.Fil: 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"; Argentina. Universidad Politécnica de Cartagena; EspañaFil: Lopez Cascales, Jose Javier. Universidad Politécnica de Cartagena; Españ
Modeling DMPC lipid membranes with SIRAH force-field
Coarse-grained simulation schemes are increasingly gaining popularity in the scientific community because of the significant speed up granted, allowing a considerable expansion of the accessible time and size scales accessible to molecular simulations. However, the number of compatible force fields capable of representing ensembles containing different molecular species (i.e., Protein, DNA, etc) is still limited. Here, we present a set of parameters and simplified representation for lipids compatible with the SIRAH force field for coarse-grained simulations (http://www.sirahff.com). We show that the present model not only achieves a correct reproduction of structural parameters as area per lipid and thickness, but also dynamic descriptors such as diffusion coefficient, order parameters, and proper temperature driven variations. Adding phospholipid membranes to the existing aqueous solution, protein and DNA representations of the SIRAH force field permit considering the most common problems tackled by the biomolecular simulation community.Fil: Barrera Guisasola, Exequiel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Pasteur de Montevideo; UruguayFil: 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: 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"; ArgentinaFil: Pantano, Sergio. Instituto Pasteur de Montevideo; Urugua
Molecular dynamics simulations of glyphosate in a DPPC lipid bilayer
Extensive molecular dynamics simulations have been performed to study the effect of glyphosate (in their neutral and charged forms, GLYP and GLYP 2− , respectively) on fully hydrated DiPalmitoylPhosphatidylCholine (DPPC) lipid bilayer. First, we calculated the free energy profile (using the Umbrella Sampling technique) for both states of charge of glyphosate. The minimum value for the free energy for GLYP is ∼−60 kJ mol −1 located at z = ±1.7 nm (from the lipid bilayer center), and there is almost no maximum at the center of the lipid bilayer. By contrast, the minimum for GLYP 2− is ∼−35 kJ mol −1 located at z = ± 1.4 nm (from the lipid bilayer center), and the maximum reaches ∼35 kJ mol −1 at the center of the lipid bilayer. Then, different lipid bilayer properties were analyzed for different glyphosate:lipid (G:L) ratios. The mean area per lipid was slightly affected, increasing only 5% (in the presence of glyphosate at high concentrations), which is in agreement with the slight decrease in deuterium order parameters. As for the thickness of the bilayer, it is observed that the state of charge produces opposite effects. On one hand, the neutral state produces an increase in the thickness of the lipid bilayer; on the other, the charged form produces a decrease in the thickness, which not depend linearly on the G:L ratios, either. The orientation of the DPPC head groups is practically unaffected throughout the range of the G:L ratios studied. Finally, the mobility of the lipids of the bilayer is strongly affected by the presence of glyphosate, considerably increasing its lateral diffusion coefficient noteworthy (one order of magnitude), with increasing G:L ratio.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: Lopez Cascales, Jose Javier. Univerdidad Politécnica de Cartagena; EspañaFil: 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
The dynamic action mechanism of small cationic antimicrobial peptides
Antimicrobial peptides form part of the immune system as protection against the action of external pathogens. The differences that exist between mammalian and microbial cell membrane architecturesare key aspects of the ability of these peptides to discriminate between pathogens and host cells. Given that the pathogen membrane is the non-specific target of these cationic peptides, different molecularmechanisms have been suggested to describe the rules that permit them to distinguish between pathogens and mammalian cells. In this context, and setting aside the old fashion idea that cationic peptides act through one mechanism alone, this work will provide insight into the molecular action mechanism of small antimicrobial peptides, based on molecular dynamics simulations of phospholipid bilayers that mimic different cell membrane architectures. After measuring different properties of theselipid bilayers, in the absence and presence of peptides, a four-step action mechanism was suggested on the basis of the formation of phospholipid rafts induced by the presence of these cationic peptides. Thus, this work shows how differences in the bending modulus (k b ) of these lipid rafts and differences in the free energy profiles (DG(z)) associated with the insertion of these peptides into these lipid rafts are key aspects for explaining the action mechanism of these cationic peptides at the molecular level.Fil: Lopez Cascales, J. J.. Universidad Politecnica de Cartagena; EspañaFil: Garro, Adriana. Universidad Politecnica de Cartagena; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Porasso, Rodolfo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Matemática Aplicada de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Universidad Politecnica de Cartagena; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentin
Influence of Lipid Composition on the Insertion Process of Glyphosate into Membranes: A Thermodynamic Study
In this work, molecular dynamics simulations were applied to investigate the influence of lipid composition of the model membrane on the insertion of glyphosate (in its charged state, GLYP2-). The profiles of free energy, entropy and enthalpy were obtained through umbrella sampling calculations, for lipid bilayers composed by only 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC), only 1,2-dipalmitoyl-sn-glycerol-3-phosphoserine (DPPS) or a symmetric binary mixture of DPPC and DPPS. In general, the location, the values of minima and maxima of the free energy, and the trend of free energy profiles are influenced by the lipid composition of the lipid bilayer. The driving force in the glyphosate insertion process depends on the lipid composition of the membrane model. If the lipid bilayer is composed solely of DPPS or DPPC, GLYP2- insertion is driven by a favorable enthalpic change. However, if the membrane is composed of a mixture of both lipids, this process is driven by a favorable entropic change. In the lipid bilayer containing DPPS, the glyphosate was found to penetrate hydrated and coordinated with Na+ ions, in contrast to the pure zwitterionic lipid bilayer which penetrated only hydrated. This effect is independent of the concentration of sodium ions present in the bulk solution.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: López Cascales, J. J.. Universidad Politécnica de Cartagena; EspañaFil: 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
Theoretical and Experimental Study of Inclusion Complexes of β-Cyclodextrins with Chalcone and 2′,4′-Dihydroxychalcone
The inclusion complexes formed by chalcone and 2′,4′-dihydroxychalcone with β-cyclodextrin have been studied combining experimental (phase solubility diagrams, Fourier transform infrared spectroscopy) and molecular modeling (molecular dynamics, quantum mechanics/molecular mechanics calculations) techniques. The formation constants of the complexes were determined at different temperatures, and the thermodynamic parameters of the process were obtained. The inclusion of chalcone in β-cyclodextrin is an exothermic process, while the inclusion of 2′,4′-dihydroxychalcone is endothermic. Free energy profiles, derived from umbrella sampling using molecular dynamics simulations, were constructed to analyze the binding affinity and the complexation reaction at a molecular level. Hybrid QM/MM calculations were also employed to obtain a better description of the energetic and structural aspects of the complexes. The intermolecular interactions that stabilize both inclusion complexes were characterized by means of quantum atoms in molecules theory and reduce density gradient method. The calculated interactions were experimentally observed using FTIR. (Figure Presented).Fil: Sancho, Matias Israel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: 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"; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentin
Pseudorotaxane formation affected by stereo-electronic effects: A theoretical and experimental study
We report a theoretical and experimental study on different complexes of pseudorotaxanes possessing pyridine axles. In order to evaluate the stereo-electronic effects of the methyl substituents in the pyridine ring, complexes with different substitution patterns were synthesized. In this way, it was possible to analyze the different behaviors of these complexes according to the positions of their methyl substituents. Combined techniques of molecular dynamics and quantum mechanical calculations with the help of molecular electrostatic potentials for a simpler visualization of the electronic effects were employed. We have sought experimental support of NMR spectroscopy analysis to corroborate the conclusions obtained from the molecular simulations. Our results not only clearly demonstrate that both electronic and steric effects play key roles in the feasibility of the formation of such complexes, but also the simulations reported here might predict the degree of difficulty of their formation. The combination of computational techniques employed here seems to be an excellent approach to be able to predict whether or not a complex can be formed and with what degree of difficulty. In addition, our experimental and theoretical results have allowed us to visualize the formation of external complexes in the rotaxanes reported here. In this case, the use of bolaforms with trimethylammonium groups at both ends was very useful to evaluate in detail the formation of the so-called external complexes in these systems.Fil: 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"; ArgentinaFil: Sancho, Matias Israel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Parajó, Mercedes. Universidad de Santiago de Compostela; EspañaFil: García Río, Luis. Universidad de Santiago de Compostela; EspañaFil: Enriz, Ricardo 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