Characterization of an anionic membrane mimetic with natural phospholipid content and magnetic orienting capabilities

Muñoz-Gacitúa, D.; Monroy-Cárdenas, Matías; Araya‐Maturana, Ramiro; Weiss-López, Boris

doi:10.1016/j.molliq.2020.114616

Cited by 2 publications

(4 citation statements)

References 55 publications

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“…On NVT ensemble simulations, a temperature of was maintained with a modified Berendsen thermostat 53 , keeping the bilayer and bulk content in separated thermostats, both with a time constant of 1.0 ps. This was done to improve the reproducibility of H-NMR spectroscopic results 42 . With NPT ensemble simulations, the same temperature schema was kept, while adding pressure control with a semi-isotropic Berendsen barostat 54 , keeping the system at 1 bar in all directions with a time constant of 1.0 ps for both xy-plane and z-axis.…”

Section: Methodsmentioning

confidence: 99%

“…In this way, by synthesizing multiples copies of the TP1 peptide with deuterium-labeled amino acids in different fragments and inserting these into an SDS-based (sodium dodecanoyl sulfate) synthetic bilayer sample 41 , we can obtain a set of order parameters belonging to each of the deuterium-labeled amino acids. We used this information, along with a calibrated molecular dynamics (MD) simulation model 42 , to calculate an equilibrium dynamic structure for the TP1 peptide inserted in the transmembrane domain.…”

Section: Introductionmentioning

confidence: 99%

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Insights into the equilibrium structure and translocation mechanism of TP1, a spontaneous membrane-translocating peptide

Muñoz-Gacitúa

Guzmán²,

Weiss-López³

2022

Sci Rep

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Crossing the cellular membrane is one of the main barriers during drug discovery; many potential drugs are rejected for their inability to integrate into the intracell fluid. Although many solutions have been proposed to overcome this barrier, arguably the most promising solution is the use of cell-penetrating peptides. Recently, an array of hydrophobic penetrating peptides was discovered via high throughput screening which proved to be able to cross the membrane passively, and although these peptides proved to be effective at penetrating the cell, the details behind the underlying mechanism of this process remain unknown. In this study, we developed a method to find the equilibrium structure at the transmembrane domain of TP1, a hydrophobic penetrating peptide. In this method, we selectively deuterium-label amino acids in the peptidic chain, and employ results of $$^2$$ 2 H-NMR spectroscopy to find a molecular dynamics simulation of the peptide that reproduces the experimental results. Effectively finding the equilibrium orientation and dynamics of the peptide in the membrane. We employed this equilibrium structure to simulate the entire translocation mechanism and found that after the peptide reaches its equilibrium structure, it must undergo a two-step mechanism in order to completely translocate the membrane, each step involving the flip-flop of each arginine residue in the peptide. This leads us to conclude that the RLLR motif is essential for the translocating activity of the peptide.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insights into the equilibrium structure and translocation mechanism of TP1, a spontaneous membrane-translocating peptide

Muñoz-Gacitúa

Guzmán²,

Weiss-López³

2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…On NVT ensemble simulations, a temperature of 37 • C was maintained with a modified Berendsen thermostat 32 , keeping the bilayer and bulk content in separated thermostats, both with a time constant of 1.0 ps. This was done to improve the reproducibility of 2 H-NMR spectroscopic results 22 . With NPT ensemble simulations, the same temperature schema was kept, while adding pressure control with a semi-isotropic Berendsen barostat 33 , keeping the system at 1 bar in all directions with a time constant of 1.0 ps for both xy-plane and z-axis.…”

Section: Molecular Dynamicsmentioning

confidence: 99%

“…In this way, by synthesizing multiples copies of the TP1 peptide with deuterium-labeled amino acids in different fragments and inserting these into an SDS-based (Sodium dodecanoyl sulfate) synthetic bilayer sample 21 , we can obtain a set of order parameters belonging to each of the deuterium-labeled amino acids. We used this information, along with a calibrated molecular dynamics (MD) simulation model 22 , to calculate an equilibrium dynamic structure for the TP1 peptide inserted in the transmembrane domain. Furthermore, with this equilibrium structure, we calibrated an MD simulation of the TP1 peptide translocating the same SDS-based synthetic bilayer, which we employed to propose a detailed mechanism, with a potential of mean force (PMF) profile included.…”

Section: Introductionmentioning

confidence: 99%

Exploring the translocation mechanism of a hydrophobic penetrating peptide

Muñoz-Gacitúa

Guzman

Weiss-López

2022

Preprint

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Crossing the cellular membrane is one of the main barriers during drug discovery; many potential drugs are rejected for their inability to integrate into the intracell fluid. Although many solutions have been proposed to overcome this barrier, arguably the most promising solution is the use of cell-penetrating peptides. These are short peptides that can internalize into the cell while carrying a cargo. Until few years ago, most of the development was focused on cationic penetrating peptides which enter the cell via endocytosis. This mechanism has the unfortunate consequence of leaving the cargo entrapped inside the endocyte. However, hydrophobic penetrating peptides present themselves as a solution to this problem since they can translocate the membrane passively and directly. Recently, an array of hydrophobic penetrating peptides was discovered via high throughput screening which proved to be able to cross the membrane passively, and although these peptides proved to be effective at penetrating the cell, the underlying mechanism of this process remains unsolved. In this study, we developed a method to find the equilibrium structure of a hydrophobic penetrating peptide in the transmembrane domain by selectively deuterium-labeling amino acids in the peptidic chain, and employing the results of 2H-NMR spectroscopy to find a molecular dynamics equilibrium simulation of the peptide, that reproduces the experimental results, and therefore the orientation and dynamics of the peptide in the membrane. We employed this equilibrium structure to simulate the entire translocation mechanism and found that after the peptide reaches its equilibrium structure, it must undergo a two-step mechanism in order to completely translocate the membrane, each step involving the flip-flop of each arginine residue in the peptide. This leads us to conclude that the RLLR motif is essential for the translocating activity of the peptide.

show abstract

Characterization of an anionic membrane mimetic with natural phospholipid content and magnetic orienting capabilities

Cited by 2 publications

References 55 publications

Insights into the equilibrium structure and translocation mechanism of TP1, a spontaneous membrane-translocating peptide

Insights into the equilibrium structure and translocation mechanism of TP1, a spontaneous membrane-translocating peptide

Exploring the translocation mechanism of a hydrophobic penetrating peptide

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