Atomistic Molecular Simulations Suggest a Kinetic Model for Membrane Translocation by Arginine-Rich Peptides

Sun, Delin; Forsman, Jan; Woodward, Clifford E.

doi:10.1021/acs.jpcb.5b08072

Cited by 33 publications

(34 citation statements)

References 42 publications

(80 reference statements)

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“…33 These pores are predicted to be strongly kinetically stabilized by Arg-rich peptides, while no such effect occurs for Lys-rich peptides. [48][49][50] Simulation results are supported by a number of experimental studies. For example, time fluorescence shift measurements have shown that longer polypeptides penetrate deeper than shorter peptides in the bilayer.…”

Section: Membrane Aggregation and Cell Penetration Of Arginine-rich Pmentioning

confidence: 67%

Arginine “Magic”: Guanidinium Like-Charge Ion Pairing from Aqueous Salts to Cell Penetrating Peptides

et al. 2018

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It is a textbook knowledge that charges of the same polarity repel each other. For two monovalent ions in the gas phase at a close contact this repulsive interaction amounts to hundreds of kilojoules per mole. In aqueous solutions, however, this Coulomb repulsion is strongly attenuated by a factor equal to the dielectric constant of the medium. The residual repulsion, which now amounts only to units of kilojoules per mole, may be in principle offset by attractive interactions. Probably the smallest cationic pair, where a combination of dispersion and cavitation forces overwhelms the Coulomb repulsion, consists of two guanidinium ions in water. Indeed, by a combination of molecular dynamics with electronic structure calculations and electrophoretic, as well as spectroscopic, experiments, we have demonstrated that aqueous guanidinium cations form (weakly) thermodynamically stable like-charge ion pairs. The importance of pairing of guanidinium cations in aqueous solutions goes beyond a mere physical curiosity, since it has significant biochemical implications. Guanidinium chloride is known to be an efficient and flexible protein denaturant. This is due to the ability of the orientationally amphiphilic guanidinium cations to disrupt various secondary structural motifs of proteins by pairing promiscuously with both hydrophobic and hydrophilic groups, including guanidinium-containing side chains of arginines. The fact that the cationic guanidinium moiety forms the dominant part of the arginine side chain implies that the like-charge ion pairing may also play a role for interactions between peptides and proteins. Indeed, arginine-arginine pairing has been frequently found in structural protein databases. In particular, when strengthened by a presence of negatively charged glutamate, aspartate, or C-terminal carboxylic groups, this binding motif helps to stabilize peptide or protein dimers and is also found in or near active sites of several enzymes. The like-charge pairing of the guanidinium side-chain groups may also hold the key to the understanding of the arginine "magic", that is, the extraordinary ability of arginine-rich polypeptides to passively penetrate across cellular membranes. Unlike polylysines, which are also highly cationic but lack the ease in crossing membranes, polyarginines do not exhibit mutual repulsion. Instead, they accumulate at the membrane, weaken it, and might eventually cross in a concerted, "train-like" manner. This behavior of arginine-rich cell penetrating peptides can be exploited when devising smart strategies how to deliver in a targeted way molecular cargos into the cell.

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Section: Membrane Aggregation and Cell Penetration Of Arginine-rich Pmentioning

confidence: 67%

Arginine “Magic”: Guanidinium Like-Charge Ion Pairing from Aqueous Salts to Cell Penetrating Peptides

et al. 2018

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“…For example, the mechanical stress created by peptide aggregation is also considered to produce pores to relieve membrane line tension. 25 , 43 …”

Section: Resultsmentioning

confidence: 99%

“…Fuertes et al 24 suggested that membrane-active peptides can serve as inducers and stabilizers of pores, the formation of which may also be induced by mechanical or electrical tensions. Sun et al 25 studied the Arg-rich CPPs of octa-arginine peptides. They applied external tension on the lipids to induce a pore for peptide translocation.…”

Section: Introductionmentioning

confidence: 99%

Insights into Membrane Translocation of Protegrin Antimicrobial Peptides by Multistep Molecular Dynamics Simulations

Lai

Kaznessis

2018

ACS Omega

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Protegrin-1 (PG-1) is a cationic arginine-rich antimicrobial peptide. It is widely accepted that PG-1 induces membrane disruption by forming pores that lead to cell death. However, the insertion mechanism for these highly cationic peptides into the hydrophobic membrane environment is still poorly understood at the molecular scale. It has previously been determined that the association of arginine guanidinium and lipid phosphate groups results in strong bidentate bonds that stabilize peptide–lipid complexes. It has also been suggested that arginine residues are able to drag phosphate groups as they insert inside the membrane to form a toroidal pore. However, whether bidentate bonds play a significant role in inducing a pore formation remains unclear. To investigate the role of bidentate complexes in PG-1 translocation, we conducted molecular dynamics simulations. Two computational electroporation methods were implemented to examine the translocation process. We found that PG-1 could insert into the membrane, provided the external electric potential is large enough to first induce a water column or a pore within the lipid bilayer membrane. We also found that the highly charged PG-1 is capable in itself of inducing molecular electroporation. Substitution of arginines with charge-equivalent lysines showed a markedly reduced tendency for insertion. This indicates that the guanidinium group likely facilitates PG-1 translocation. Potential of mean force calculations suggests that peptide insertion inside the hydrophobic environment of the membrane core is not favored. We found that formation of a water column or a pore might be a prerequisite for PG-1 translocation. We also found that PG-1 can stabilize the pore after insertion. We suggest that PG-1 could be a pore inducer and stabilizer. This work sheds some light on PG-1 translocation mechanisms at the molecular level. Methods presented in this study may be extended to other arginine-rich antimicrobial and cell-penetrating peptides.

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“…RCs have been proposed, including a RC that steers the lipids collectively in lateral direction away from the pore center, 24 a lipid flip-flop coordinate, steering a single lipid head group towards the membrane core, 13,[25][26][27] or the mean solvent density within a membrane-spanning cylinder. 28 In a systematic comparison of RCs of pore formation, we found that pulling along these established RCs for pore nucleation efficiently triggered pore formation.…”

Section: Introductionmentioning

confidence: 99%

A joint reaction coordinate for computing the free energy landscape of pore nucleation and pore expansion in lipid membranes

Hub

2020

Preprint

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Topological transitions of membranes, such as pore formation or membrane fusion, play key roles in biology, biotechnology, and in medical applications. Calculating the related free energy landscapes has been complicated by the fact that such processes involve a sequence of transitions along highly distinct directions in conformational space, making it difficult to define good reaction coordinates (RCs) for the overall process. In this study, we present a new RC capable of driving both pore nucleation and pore expansion in lipid membranes. The potential of mean force (PMF) along the RC computed with molecular dynamics (MD) simulations provides a comprehensive view on the free-energy landscape of pore formation, including a barrier for pore nucleation, the size, free energy, and metastability of the open pore, and the energetic cost for further pore expansion against the line tension of the pore rim. We illustrate the RC by quantifying the effects (i) of simulation system size and (ii) of the addition of dimethyl sulfoxide (DMSO) on the free energy landscape of pore formation. PMF calculations along the RC provide mechanistic and energetic understanding of pore formation, hence they will be useful to rationalize the effects of membrane-active peptides, electric fields, and membrane composition on transmembrane pores.Graphical TOC Entry

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Atomistic Molecular Simulations Suggest a Kinetic Model for Membrane Translocation by Arginine-Rich Peptides

Cited by 33 publications

References 42 publications

Arginine “Magic”: Guanidinium Like-Charge Ion Pairing from Aqueous Salts to Cell Penetrating Peptides

Arginine “Magic”: Guanidinium Like-Charge Ion Pairing from Aqueous Salts to Cell Penetrating Peptides

Insights into Membrane Translocation of Protegrin Antimicrobial Peptides by Multistep Molecular Dynamics Simulations

A joint reaction coordinate for computing the free energy landscape of pore nucleation and pore expansion in lipid membranes

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