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Concerted Rolling and Penetration of Peptides during Membrane Binding.

ABSTRACT: Peptide binding to membranes is common and fundamental in biochemistry and biophysics and critical for applications ranging from drug delivery to the treatment of bacterial infections. However, it is largely unclear, from a theoretical point of view, what peptides of different sequences and structures share in the membrane-binding and insertion process. In this work, we analyze three prototypical membrane-binding peptides (α-helical magainin, PGLa, and β-hairpin tachyplesin) during membrane binding, using molecular details provided by Markov state modeling and microsecond-long molecular dynamics simulations. By leveraging both geometric and data-driven collective variables that capture the essential physics of the amphiphilic and cationic peptide-membrane interactions, we reveal how the slowest kinetic process of membrane binding is the dynamic rolling of the peptide from an attached to a fully bound state. These results not only add fundamental knowledge of the theory of how peptides bind to biological membranes but also open new avenues to study general peptides in more complex environments for further applications.

SUBMITTER: Remington JM

PROVIDER: S-EPMC9281202 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Concerted Rolling and Penetration of Peptides during Membrane Binding.

Remington Jacob M JM Ferrell Jonathon B JB Schneebeli Severin T ST Li Jianing J

Journal of chemical theory and computation 20220504 6

Peptide binding to membranes is common and fundamental in biochemistry and biophysics and critical for applications ranging from drug delivery to the treatment of bacterial infections. However, it is largely unclear, from a theoretical point of view, what peptides of different sequences and structures share in the membrane-binding and insertion process. In this work, we analyze three prototypical membrane-binding peptides (α-helical magainin, PGLa, and β-hairpin tachyplesin) during membrane bind ...[more]

PMID: 35507824

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Project description:The novel neuroproteasome is localized to the neuronal plasma membrane to degrade intracellular proteins into peptides that are released to the extracellular space. Selective inhibition of this neuronal membrane proteasome (NMP) complex ceased the release of peptides and rapidly attenuated neuronal transmission. Based on these findings, we hypothesize that these neuron-specific peptides mediate a novel form of communication through unique peptide-receptor interactions to promote intracellular signaling cascades relevant to neuronal development and function. Our work indicates that NMP peptides can rapidly induce N-methyl-D-aspartate receptor (NMDAR)-dependent calcium influx from dendrites to the soma, leading to rapid and sustained phosphorylation of the well-defined activity-dependent transcription factor cAMP response element-binding protein (CREB). We also determined that the gene expression program drastically changes upon NMP peptide treatment of neurons with an increase in expression of immediate early genes (e.g., Fos, Npas4, Egr4) known to have critical neuroregulatory roles. These data support our current thinking that NMP peptides are endogenous and selective activators of synaptic NMDA receptors and are critical for promoting activity-dependent gene expression. This pathway is orthogonal to the classic neurotransmitters previously described to activate NMDARs and points to NMP and its resulting peptides as key contributors to the development and function of the nervous system. However, the unique peptide sequences leading to neuronal activation are still poorly understood. Here, we show that the NMP peptides have tremendous sequence diversity through an unbiased peptidomic approach, and the current ongoing effort is to identify unique active peptide sequences with distinct receptor specificity. Elucidating the mechanism of the NMP and its active peptide products is crucial to understanding the role of this novel signaling process in the nervous system.

Project description:The lipid composition of the cellular membrane plays an important role in a number of biological processes including the binding of membrane-active peptides. Characterization of membrane binding remains challenging, due to the technical limitations associated with the use of standard biophysical techniques and available membrane models. Here, we investigate the lipid binding properties of two membrane-active peptides, VSTx1, a well characterized ion-channel inhibitor, identified from spider venom, that preferentially binds to anionic lipid mixtures, and AA139 an antimicrobial ?-hairpin peptide with uncharacterised lipid binding properties, currently in pre-clinical development. The lipid binding properties of these peptides are elucidated using nanodiscs formed by both linear and circularized (sortase-mediated) forms of a membrane scaffold protein (MSP1D1?H5). We find that nanodiscs formed by circularized MSPs-in contrast to those formed by linear MSPs-are sufficiently stable under sample conditions typically used for biophysical measurements (including lipid composition, a range of buffers, temperatures and concentrations). Using these circularized nanodiscs, we are able to extract detailed thermodynamic data using isothermal titration calorimetry (ITC) as well as atomic resolution mapping of the lipid binding interfaces of our isotope labeled peptides using solution-state, heteronuclear, nuclear magnetic resonance (NMR) spectroscopy. This represents a novel and general approach for elucidating the thermodynamics and molecular interface of membrane-active peptides toward flat lipid bilayers of variable composition. Our approach is validated by first determining the thermodynamic parameters and binding interface of VSTx1 toward the lipid bilayer, which shows good agreement with previous studies using lipid micelles and liposomes. The method is then applied to AA139, where the membrane binding properties are unknown. This characterization, involved solving the high-resolution structure of AA139 in solution using NMR spectroscopy and the development of a suitable expression system for isotope labeling. AA139 was found to bind exclusively to anionic membranes with moderate affinity (K d~low ?M), and was found to have a lipid binding interface involving the termini of the ?-hairpin structure. The preference of AA139 for anionic lipids supports a role for membrane binding in the mode-of-action of this peptide, which is also consistent with its higher inhibitory activity against bacterial cells compared to mammalian cells. The described approach is a powerful method for investigation of the membrane binding properties of this important class of molecules.

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Concerted Rolling and Penetration of Peptides during Membrane Binding.

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Concerted Rolling and Penetration of Peptides during Membrane Binding.

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