Dataset Information

De novo aggregation of Alzheimer's A?25-35 peptides in a lipid bilayer.

ABSTRACT: A potential mechanism of cytotoxicity attributed to Alzheimer's A? peptides postulates that their aggregation disrupts membrane structure causing uncontrollable permeation of Ca²⁺ ions. To gain molecular insights into these processes, we have performed all-atom explicit solvent replica exchange with solute tempering molecular dynamics simulations probing aggregation of the naturally occurring A? fragment A?25-35 within the DMPC lipid bilayer. To compare the impact produced on the bilayer by A?25-35 oligomers and monomers, we used as a control our previous simulations, which explored binding of A?25-35 monomers to the same bilayer. We found that compared to monomeric species aggregation results in much deeper insertion of A?25-35 peptides into the bilayer hydrophobic core causing more pronounced disruption in its structure. A?25-35 peptides aggregate by incorporating monomer-like structures with stable C-terminal helix. As a result the A?25-35 dimer features unusual helix head-to-tail topology supported by a parallel off-registry interface. Such topology affords further growth of an aggregate by recruiting additional peptides. Free energy landscape reveals that inserted dimers represent the dominant equilibrium state augmented by two metastable states associated with surface bound dimers and inserted monomers. Using the free energy landscape we propose the pathway of A?25-35 binding, aggregation, and insertion into the lipid bilayer.

SUBMITTER: Smith AK

PROVIDER: S-EPMC6509337 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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De novo aggregation of Alzheimer's Aβ25-35 peptides in a lipid bilayer.

Smith Amy K AK Klimov Dmitri K DK

Scientific reports 20190509 1

A potential mechanism of cytotoxicity attributed to Alzheimer's Aβ peptides postulates that their aggregation disrupts membrane structure causing uncontrollable permeation of Ca<sup>2+</sup> ions. To gain molecular insights into these processes, we have performed all-atom explicit solvent replica exchange with solute tempering molecular dynamics simulations probing aggregation of the naturally occurring Aβ fragment Aβ25-35 within the DMPC lipid bilayer. To compare the impact produced on the bila ...[more]

PMID: 31073226

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Project description:The origin of novel genes and beneficial functions is of fundamental interest in evolutionary biology. New genes can originate from different mechanisms, including horizontal gene transfer, duplication-divergence, and de novo from noncoding DNA sequences. Comparative genomics has generated strong evidence for de novo emergence of genes in various organisms, but experimental demonstration of this process has been limited to localized randomization in preexisting structural scaffolds. This bypasses the basic requirement of de novo gene emergence, i.e., lack of an ancestral gene. We constructed highly diverse plasmid libraries encoding randomly generated open reading frames and expressed them in Escherichia coli to identify short peptides that could confer a beneficial and selectable phenotype in vivo (in a living cell). Selections on antibiotic-containing agar plates resulted in the identification of three peptides that increased aminoglycoside resistance up to 48-fold. Combining genetic and functional analyses, we show that the peptides are highly hydrophobic, and by inserting into the membrane, they reduce membrane potential, decrease aminoglycoside uptake, and thereby confer high-level resistance. This study demonstrates that randomized DNA sequences can encode peptides that confer selective benefits and illustrates how expression of random sequences could spark the origination of new genes. In addition, our results also show that this question can be addressed experimentally by expression of highly diverse sequence libraries and subsequent selection for specific functions, such as resistance to toxic compounds, the ability to rescue auxotrophic/temperature-sensitive mutants, and growth on normally nonused carbon sources, allowing the exploration of many different phenotypes.IMPORTANCEDe novo gene origination from nonfunctional DNA sequences was long assumed to be implausible. However, recent studies have shown that large fractions of genomic noncoding DNA are transcribed and translated, potentially generating new genes. Experimental validation of this process so far has been limited to comparative genomics, in vitro selections, or partial randomizations. Here, we describe selection of novel peptides in vivo using fully random synthetic expression libraries. The peptides confer aminoglycoside resistance by inserting into the bacterial membrane and thereby partly reducing membrane potential and decreasing drug uptake. Our results show that beneficial peptides can be selected from random sequence pools in vivo and support the idea that expression of noncoding sequences could spark the origination of new genes.

Dataset Information

De novo aggregation of Alzheimer's A?25-35 peptides in a lipid bilayer.

Publications

De novo aggregation of Alzheimer's Aβ25-35 peptides in a lipid bilayer.

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