Mechanisms of Membrane Pore Formation by Amyloidogenic Peptides in Amyotrophic Lateral Sclerosis

Chen, Charles H.; Khan, Ayesha; Huang, Joseph Jen‐Tse; Ulmschneider, Martin B.

doi:10.1002/chem.201601765

Cited by 12 publications

(11 citation statements)

References 20 publications

(37 reference statements)

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“…Here, we report a new methodology that uses unbiased atomic detail folding-partitioning MD simulations to guide rational de novo AMP design. We have previously shown that MD simulations in the multimicrosecond regime are sufficient to capture peptide folding, insertion, and spontaneous oligomerization into structural assemblies in the bilayer at atomic detail. − In this approach, fully flexible peptides are allowed to freely assemble and dissociate in the bilayer, thus revealing the structural ensemble present at equilibrium . Like an equivalent laboratory experiment, this approach is completely unbiased.…”

Section: Introductionmentioning

confidence: 99%

Simulation-Guided Rational de Novo Design of a Small Pore-Forming Antimicrobial Peptide

et al. 2019

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In the age of failing small-molecule antibiotics, tapping the near-infinite structural and chemical repertoire of antimicrobial peptides (AMPs) offers one of the most promising routes toward developing next-generation antibacterial compounds. One of the key impediments en route is the lack of methodologies for systematic rational design and optimization of new AMPs. Here we present a new simulation-guided rational design approach and apply it to develop a potent new AMP. We show that unbiased atomic detail molecular dynamics (MD) simulations are able to predict structures formed by evolving peptide designs enabling structure-based rational fine-tuning of functional properties. Starting from a 14-residue poly leucine template we demonstrate the design of a minimalistic potent new AMP. Consisting of only four types of amino acids (LDKA), this peptide forms large pores in microbial membranes at very low peptide-to-lipid ratios (1:1000) and exhibits low micromolar activity against common Gram-positive and Gram-negative pathogenic bacteria. Remarkably, the four amino acids were sufficient to encode preferential poration of bacterial membranes with negligible damage to red blood cells at bactericidal concentrations. As the sequence is too short to span cellular membranes, pores are formed by stacking of channels in each bilayer leaflet.

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Section: Introductionmentioning

confidence: 99%

Simulation-Guided Rational de Novo Design of a Small Pore-Forming Antimicrobial Peptide

et al. 2019

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“…This allows all simulation to be run at 120 °C, increasing pore-formation kinetics. We have previously demonstrated that elevating the temperature does not change conformational equilibria or partitioning free energies of helical membrane-active peptides, provided they are stable against thermal denaturation (see Supplement); however, the vast increase in sampling kinetics at high temperatures allows simulation of peptide folding, bilayer partitioning, and pore assembly without the need for advanced sampling techniques that require additional information or may bias the system 24,47,53,99-103 .…”

Section: Methodsmentioning

confidence: 99%

Rational tuning of a membrane-perforating antimicrobial peptide to selectively target membranes of different lipid composition

Chen

Starr

Guha

et al. 2020

Preprint

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The use of designed antimicrobial peptides as drugs has been impeded by the absence of simple sequence-structure-function relationships and design rules. We demonstrate that the combination of high-throughput library screening with atomistic computer simulations can successfully address this challenge by tuning a previously developed general pore forming peptide into a selective pore former for different lipid types. A library of 2,916 peptides was designed based on the LDKA template. The library peptides were synthesized and screened using a high-throughput orthogonal vesicle leakage assay. Nine different LDKA variants that have unique activity were selected, sequenced, synthesized, and characterized. Despite the minor sequence changes, each of these peptides has unique functional properties, forming either small or large pores and being selective for either neutral or anionic lipid bilayers. Predicting the propensity to aggregate and assemble in a given environment from sequence alone holds the key to functional prediction of membrane permeabilization.

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“…This allows all simulation to be run at 120 °C, increasing pore-formation kinetics. We have previously demonstrated that elevating the temperature does not change conformational equilibria or partitioning free energies of helical A u t h o r a c c e p t e d m a n u s c r i p t membrane-active peptides, provided they are stable against thermal denaturation (Figure S1 and Table S2); however, the vast increase in sampling kinetics at high temperatures allows simulation of peptide folding, bilayer partitioning, and pore assembly without the need for advanced sampling techniques that require additional information or may bias the system (Ulmschneider and Ulmschneider 2008;Ulmschneider et al 2010;Ulmschneider et al 2011;Ulmschneider et al 2014;Chen et al 2014;Chen et al 2016;Chen et al 2019).…”

Section: Macromolecule Release Assaymentioning

confidence: 99%

Tuning of a Membrane-Perforating Antimicrobial Peptide to Selectively Target Membranes of Different Lipid Composition

et al. 2021

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The use of designed antimicrobial peptides as drugs has been impeded by the absence of simple sequence-structure-function relationships and design rules. The likely cause is that many of these peptides permeabilize membranes via highly disordered, heterogeneous mechanisms, forming aggregates without well-defined tertiary or secondary structure. We suggest that the combination of high-throughput library screening with atomistic computer simulations can successfully address this challenge by tuning a previously developed general pore forming peptide into a selective pore former for different lipid types. A library of 2,916 peptides was designed based on the LDKA template. The library peptides were synthesized and screened using a high-throughput orthogonal vesicle leakage assay. Dyes of different sizes were entrapped inside vesicles with varying lipid composition to simultaneously screen for both pore size and affinity for negatively charged and neutral lipid membranes. From this screen, nine different LDKA variants that have unique activity were selected, sequenced, synthesized, and characterized. Despite the minor sequence changes, each of these peptides has unique functional properties, forming either small or large pores and being selective for either neutral or anionic lipid bilayers. Long-scale, unbiased atomistic molecular dynamics (MD) simulations directly reveal that rather than rigid, well-defined pores, these peptides can form a large repertoire of functional dynamic and heterogeneous aggregates, strongly affected by single mutations. Predicting the propensity to aggregate and assemble in a given environment from sequence alone holds the key to functional prediction of membrane permeabilization.

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Mechanisms of Membrane Pore Formation by Amyloidogenic Peptides in Amyotrophic Lateral Sclerosis

Cited by 12 publications

References 20 publications

Simulation-Guided Rational de Novo Design of a Small Pore-Forming Antimicrobial Peptide

Simulation-Guided Rational de Novo Design of a Small Pore-Forming Antimicrobial Peptide

Rational tuning of a membrane-perforating antimicrobial peptide to selectively target membranes of different lipid composition

Tuning of a Membrane-Perforating Antimicrobial Peptide to Selectively Target Membranes of Different Lipid Composition

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