Indolicidin Binding Induces Thinning of a Lipid Bilayer

Neale, Chris; Hsu, Jenny C.Y.; Yip, Christopher M.; Pomès, Régis

doi:10.1016/j.bpj.2014.02.031

Cited by 88 publications

(78 citation statements)

References 25 publications

(28 reference statements)

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“…In contrast, the ⌬⌬F overtone profiles in Fig. 1B II are much more similar to the pore formation with the surface adsorption mechanism of PG-1 than the profiles reported by Wang et al (15) for membrane thinning caused by surface adsorption (21). This is likely due to the inclusion of the anionic POPG at a 3:1 mol ratio of PC:PG in our SLBs.…”

Section: Discussioncontrasting

confidence: 51%

“…They concluded that IND adsorbs at the lipid-water interface without peptide or water intercalation deep into the bilayer (15). A recent molecular dynamics simulation, which is in agreement with this result, reports IND causes thinning of a POPC lipid bilayer through adsorption at the lipid-water interface (21). In contrast, the ⌬⌬F overtone profiles in Fig.…”

Section: Discussioncontrasting

confidence: 30%

See 1 more Smart Citation

Mechanism of Four de Novo Designed Antimicrobial Peptides

Murray

Pearson

Aranjo

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanAs pathogenic bacteria become resistant to traditional antibiotics, alternate approaches such as designing and testing new potent selective antimicrobial peptides (AMP) are increasingly attractive. However, whereas much is known regarding the relationship between the AMP sequence and potency, less research has focused on developing links between AMP properties, such as design and structure, with mechanisms. Here we use four natural AMPs of varying known secondary structures and mechanisms of lipid bilayer disruption as controls to determine the mechanisms of four rationally designed AMPs with similar secondary structures and rearranged amino acid sequences. Using a Quartz Crystal Microbalance with Dissipation, we were able to differentiate between molecular models of AMP actions such as barrel-stave pore formation, toroidal pore formation, and peptide insertion mechanisms by quantifying differential frequencies throughout an oscillating supported lipid bilayer. Barrel-stave pores were identified by uniform frequency modulation, whereas toroidal pores possessed characteristic changes in oscillation frequency throughout the bilayer. The resulting modes of action demonstrate that rearrangement of an amino acid sequence of the AMP resulted in identical overall mechanisms, and that a given secondary structure did not necessarily predict mechanism. Also, increased mass addition to Gram-positive mimetic membranes from AMP disruption corresponded with lower minimum inhibitory concentrations against the Gram-positive Staphylococcus aureus.All multicellular organisms such as animals and plants protect themselves against pathogenic microbes by producing antimicrobial peptides (AMPs) 2 that selectively disrupt bacterial cell membranes (1). Although they are enormously diverse, AMPs are mainly comprised of hydrophobic and cationic amino acids that are spatially organized along the molecule. Because bacteria depend on the integrity of their anionic cell membrane, disrupting their membrane with cationic peptides could offer an alternate strategy to conventional antibiotics for killing pathogenic bacteria (2). As these pathogens become resistant to traditional antibiotics, alternate approaches such as designing and testing new potent selective antimicrobial peptides are increasingly attractive.The proper composition of amino acids, their sequential arrangement, and peptide length are essential for effective action of AMPs (3). It has been demonstrated that AMP activity is more closely tied to amino acid composition than amino acid sequence or AMP structure (4 -8). However, it has recently been shown that for the ␣-helical class of AMPs, ordering amino acids during AMP design into an imperfect amphipathic ␣-helix, a helix barrel-stave with one hydrophobic and one hydrophilic face where the hydrophobic face is disrupted by one hydrophilic amino acid, is beneficial for increasing AMP activity (9). Understanding the mechanism behind how these peptides disrupt cell membranes could benefit future designs of p...

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Section: Discussioncontrasting

confidence: 51%

Section: Discussioncontrasting

confidence: 30%

Mechanism of Four de Novo Designed Antimicrobial Peptides

Murray

Pearson

Aranjo

et al. 2016

Journal of Biological Chemistry

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“…Also, peptides tend to be flexible, with a broad range of accessible conformations; this can significantly complicate the interpretation of mutagenesis data, as even seemingly simple substitutions can significantly alter the peptides' conformation and pose relative to the membrane. This flexibility also makes AMPs challenging targets for computer simulation; their structural plasticity combined with the slow relaxation times for lipid-peptide interactions make it very hard to acquire adequate statistical sampling, even using state-of-the-art enhanced sampling methods (16,17). For these reasons, as well as their susceptibility to protease degradation in vivo and their potential toxicity to human cells (5), there has been only limited success in making AMPs into internal antibiotics (15).…”

Section: Introductionmentioning

confidence: 99%

Thermodynamics of Micelle Formation and Membrane Fusion Modulate Antimicrobial Lipopeptide Activity

Lin

Grossfield

2015

Biophysical Journal

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Antimicrobial lipopeptides (AMLPs) are antimicrobial drug candidates that preferentially target microbial membranes. One class of AMLPs, composed of cationic tetrapeptides attached to an acyl chain, have minimal inhibitory concentrations in the micromolar range against a range of bacteria and fungi. Previously, we used coarse-grained molecular dynamics simulations and free energy methods to study the thermodynamics of their interaction with membranes in their monomeric state. Here, we extended the study to the biologically relevant micellar state, using, to our knowledge, a novel reaction coordinate based on hydrophobic contacts. Using umbrella sampling along this reaction coordinate, we identified the critical transition states when micelles insert into membranes. The results indicate that the binding of these AMLP micelles to membranes is thermodynamically favorable, but in contrast to the monomeric case, there are significant free energy barriers. The height of these free energy barriers depends on the membrane composition, suggesting that the AMLPs' ability to selectively target bacterial membranes may be as much kinetic as thermodynamic. This mechanism highlights the importance of considering oligomeric state in solution as criterion when optimizing peptides or lipopeptides as antibiotic leads.

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“…This problem is often underestimated, because even degrees of freedom that interconvert rapidly can be linked to the much slower dynamics of the entire protein (35)(36)(37). Enhanced sampling methods can improve the situation, but most advanced methods require the choice of an informative reaction coordinate, which can be very difficult to obtain.…”

Section: Introductionmentioning

confidence: 97%

Retinal Conformation Changes Rhodopsin’s Dynamic Ensemble

Leioatts

Romo

Danial

et al. 2015

Biophysical Journal

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G protein-coupled receptors are vital membrane proteins that allosterically transduce biomolecular signals across the cell membrane. However, the process by which ligand binding induces protein conformation changes is not well understood biophysically. Rhodopsin, the mammalian dim-light receptor, is a unique test case for understanding these processes because of its switch-like activity; the ligand, retinal, is bound throughout the activation cycle, switching from inverse agonist to agonist after absorbing a photon. By contrast, the ligand-free opsin is outside the activation cycle and may behave differently. We find that retinal influences rhodopsin dynamics using an ensemble of all-atom molecular dynamics simulations that in aggregate contain 100 μs of sampling. Active retinal destabilizes the inactive state of the receptor, whereas the active ensemble was more structurally homogenous. By contrast, simulations of an active-like receptor without retinal present were much more heterogeneous than those containing retinal. These results suggest allosteric processes are more complicated than a ligand inducing protein conformational changes or simply capturing a shifted ensemble as outlined in classic models of allostery.

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Indolicidin Binding Induces Thinning of a Lipid Bilayer

Cited by 88 publications

References 25 publications

Mechanism of Four de Novo Designed Antimicrobial Peptides

Mechanism of Four de Novo Designed Antimicrobial Peptides

Thermodynamics of Micelle Formation and Membrane Fusion Modulate Antimicrobial Lipopeptide Activity

Retinal Conformation Changes Rhodopsin’s Dynamic Ensemble

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