Molecular Dynamics Simulations to Study Drug Delivery Systems

Molecular dynamics simulation is a very powerful tool to understand biomolecular processes. In this chapter, we go over different applications of this methodology to drug delivery systems (DDS) carried out in the group. DDS—a formulation or a device that enables the introduction of a therapeutic substance in the body and improves its efficacy and safety by controlling the rate, time, and place of release of drugs—are an important component of drug development and therapeutics. Biocompatible nanoparticles are materials in the nanoscale that emerged as important players, improving efficacy of approved drugs, for example. The molecular understanding of the encapsulation process could be very helpful to guide the nanocarrier for a specific system. Here we discuss different applications of drug delivery carriers, such as liposomes, polymeric micelles, and polymersomes using atomistic and coarse grain (CG) molecular dynamics simulations

V-shape" molecular configuration of wax esters of jojoba oil in a Langmuir film model

The aim of the present work was to understand the interfacial properties of a complex mixture of wax esters (WEs) obtained from Jojoba oil (JO). Previously, on the basis of molecular area measurements, a hairpin structure was proposed as the hypothetical configuration of WEs, allowing their organization as compressible monolayers at the air-water interface. In the present work, we contributed with further experimental evidence by combining surface pressure (π), surface potential (ΔV), and PM-IRRAS measurements of JO monolayers and molecular dynamic simulations (MD) on a modified JO model. WEs were self-assembled in Langmuir films. Compression isotherms exhibited π lift-off at 100 Å 2 /molecule mean molecular area (A lift-off ) and a collapse point at π c ≈ 2.2 mN/m and A c ≈ 77 Å 2 /molecule. The ΔV profile reflected two dipolar reorganizations, with one of them at A > A lift-off due to the release of loosely bound water molecules and another one at A c < A < A lift-off possibly due to reorientations of a more tightly bound water population. This was consistent with the maximal SP value that was calculated according to a model that considered two populations of oriented water and was very close to the experimental value. The orientation of the ester group that was assumed in that calculation was coherent with the PM-IRRAS behavior of the carbonyl group with the C=O oriented toward the water and the C-O oriented parallel to the surface and was in accordance with their orientational angles (∼45 and ∼90°, respectively) determined by MD simulations. Taken together, the present results confirm a V shape rather than a hairpin configuration of WEs at the air-water interface.Fil: Caruso, Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; ArgentinaFil: Martini, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Pickholz, Mónica Andrea. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Perillo, Maria Angelica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; Argentin

Differential Stability of Aurein 1.2 Pores in Model Membranes of Two Probiotic Strains

Aurein 1.2 is an antimicrobial peptide from the skin secretion of an Australian frog. In the previous experimental work, we reported a differential action of aurein 1.2 on two probiotic strains Lactobacillus delbrueckii subsp. bulgaricus (CIDCA 331) and Lactobacillus delbrueckii subsp. lactis (CIDCA 133). The differences found were attributed to the bilayer compositions. Cell cultures and CIDCA 331-derived liposomes showed higher susceptibility than the ones derived from the CIDCA 133 strain, leading to content leakage and structural disruption. Here, we used molecular dynamics simulations to explore these systems at the atomistic level. We hypothesize that if the antimicrobial peptides organized themselves to form a pore, it will be more stable in membranes that emulate the CIDCA 331 strain than in those of the CIDCA 133 strain. To test this hypothesis, we simulated preassembled aurein 1.2 pores embedded into bilayer models that emulate the two probiotic strains. It was found that the general behavior of the systems depends on the composition of the membrane rather than the preassemble system characteristics. Overall, it was observed that aurein 1.2 pores are more stable in the CIDCA 331 model membranes. This fact coincides with the high susceptibility of this strain against antimicrobial peptide. In contrast, in the case of the CIDCA 133 model membranes, peptides migrate to the water-lipid interphase, the pore shrinks, and the transport of water through the pore is reduced. The tendency of glycolipids to make hydrogen bonds with peptides destabilizes the pore structures. This feature is observed to a lesser extent in CIDCA 331 due to the presence of anionic lipids. Glycolipid transverse diffusion (flip-flop) between monolayers occurs in the pore surface region in all the cases considered. These findings expand our understanding of the antimicrobial peptide resistance properties of probiotic strains.Fil: Balatti, Galo Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Domene, Carmen. University of Bath; Reino UnidoFil: Martini, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Pickholz, Mónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentin

In silico selection and evaluation of pugnins with antibacterial and anticancer activity using skin transcriptome of treefrog (Boana pugnax)

In order to combat bacterial and cancer resistance, we identified peptides (pugnins) with dual antibacterial l–anticancer activity from the Boana pugnax (B. pugnax) skin transcriptome through in silico analysis. Pugnins A and B were selected owing to their high similarity to the DS4.3 peptide, which served as a template for their alignment to the B. pugnax transcriptome, as well as their function as part of a voltage-dependent potassium channel protein. The secondary peptide structure stability in aqueous medium was evaluated as well, and after interaction with the Escherichia coli (E. coli) membrane model using molecular dynamics. These pugnins were synthesized via solid-phase synthesis strategy and verified by Reverse phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry. Subsequently, their alpha-helix structure was determined by circular dichroism, after which antibacterial tests were then performed to evaluate their antimicrobial activity. Cytotoxicity tests against cancer cells also showed selectivity of pugnin A toward breast cancer (MFC7) cells, and pugnin B toward prostate cancer (PC3) cells. Alternatively, flow cytometry revealed necrotic cell damage with a major cytotoxic effect on human keratinocytes (HaCaT) control cells. Therefore, the pugnins found in the transcriptome of B. pugnax present dual antibacterial– anticancer activity with reduced selectivity to normal eukaryotic cells.Fil: Liscano, Yamil. Universidad Santiago de Cali; Colombia. Universidad de Antioquia; ColombiaFil: Medina, Laura. Universidad de Antioquia; ColombiaFil: Oñate Garzón, Jose. Universidad Santiago de Cali; ColombiaFil: Gúzman, Fanny. Pontificia Universidad Católica de Valparaíso; ChileFil: Pickholz, Mónica Andrea. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Delgado, Jean Paul. Universidad de Antioquia; Colombi

Study of the lamellar and micellar phases of pluronic F127: A molecular dynamics approach

In this work, we analyzed the behavior of Pluronic F127 through molecular dynamics simulations at the coarse-grain level, focusing on the micellar and lamellar phases. To this aim, two initial polymer conformations were considered, S-shape and U-shape, for both simulated phases. Through the simulations, we were able to examine the structural and mechanical properties that are difficult to access through experiments. Since no transition between S and U shapes was observed in our simulations, we inferred that all single co-polymers had memory of their initial configuration. Nevertheless, most copolymers had a more complex amorphous structure, where hydrophilic beads were part of the lamellar-like core. Finally, an overall comparison of the micellar a lamellar phases showed that the lamellar thickness was in the same order of magnitude as the micelle diameter (approx. 30 nm). Therefore, high micelle concentration could lead to lamellar formation. With this new information, we could understand lamellae as orderly packed micelles.Fil: Albano, Juan Manuel Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Grillo, Damián Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Facelli, Julio C.. University of Utah; Estados UnidosFil: Ferraro, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Pickholz, Mónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentin

Electronic structure of nitrogen-carbon alloys (a-CNx) determined by photoelectron spectroscopy

The electronic structure of nitrogen-containing diamondlike films prepared by sputtering was determined by photoelectron spectroscopy. The N 1s core-level spectra are constituted by two peaks at 400.5 and 398.2 eV associated with substitutional N sp(2) in aromatic rings and N bonded to C sp(3), respectively. On increasing N, the top of the valence band suffers profound changes. The new features are identified by a comparison of the experimental spectra with theoretically calculated density of states of nitrogen-containing graphite and C3N4 structures. [S0163-1829(98)04004-1].5742536254