Antimicrobial peptides are postulated to disrupt microbial phospholipid membranes. The prevailing molecular model is based on the formation of stable or transient pores although the direct observation of the fundamental processes is lacking. By combining rational peptide design with topographical (atomic force microscopy) and chemical (nanoscale secondary ion mass spectrometry) imaging on the same samples, we show that pores formed by antimicrobial peptides in supported lipid bilayers are not necessarily limited to a particular diameter, nor they are transient, but can expand laterally at the nano-to-micrometer scale to the point of complete membrane disintegration. The results offer a mechanistic basis for membrane poration as a generic physicochemical process of cooperative and continuous peptide recruitment in the available phospholipid matrix.innate host defense | de novo protein design | nanometrology | antibiotics | nanoscopy
BackgroundThe study of biological membranes using Molecular Dynamics has become an increasingly popular means by which to investigate the interactions of proteins, peptides and potentials with lipid bilayers. These interactions often result in changes to the properties of the lipids which can modify the behaviour of the membrane. Membrainy is a unified membrane analysis tool that contains a broad spectrum of analytical techniques to enable: measurement of acyl chain order parameters; presentation of 2D surface and thickness maps; determination of lateral and axial headgroup orientations; measurement of bilayer and leaflet thickness; analysis of the annular shell surrounding membrane-embedded objects; quantification of gel percentage; time evolution of the transmembrane voltage; area per lipid calculations; and quantification of lipid mixing/demixing entropy.ResultsEach analytical component within Membrainy has been tested on a variety of lipid bilayer systems and was found to be either comparable to or an improvement upon existing software. For the analytical techniques that have no direct comparable software, our results were confirmed with experimental data.ConclusionsMembrainy is a user-friendly, intelligent membrane analysis tool that automatically interprets a variety of input formats and force fields, is compatible with both single and double bilayers, and capable of handling asymmetric bilayers and lipid flip-flopping. Membrainy has been designed for ease of use, requiring no installation or configuration and minimal user-input to operate.
Background: Direct antagonists of native antimicrobial peptide (AMP) sequences are unknown.Results: Complementary antagonistic sequences can co-fold with AMPs into functionally inert assemblies.Conclusion: Antagonists act as anti-AMPs.Significance: The findings offer a molecular rationale for anti-AMP responses with potential implications for antimicrobial resistance.
The realism and accuracy of lipid bilayer simulations through molecular dynamics (MD) are heavily dependent on the lipid composition. While the field is pushing toward implementing more heterogeneous and realistic membrane compositions, a lack of high-resolution lipidomic data prevents some membrane protein systems from being modeled with the highest level of realism. Given the additional diversity of real-world cellular membranes and protein–lipid interactions, it is still not fully understood how altering membrane complexity affects modeled membrane protein functions or if it matters over long-timescale simulations. This is especially true for organisms whose membrane environments have little to no computational study, such as the plant plasma membrane. Tackling these issues in tandem, a generalized, realistic, and asymmetric plant plasma membrane with more than 10 different lipid species is constructed herein. Classical MD simulations of pure membrane constructs were performed to evaluate how altering the compositional complexity of the membrane impacted the plant membrane properties. The apo form of a plant sugar transporter, OsSWEET2b, was inserted into membrane models where lipid diversity was calculated in either a size-dependent or size-independent manner. An adaptive sampling simulation regime validated by Markov-state models was performed to capture the gating dynamics of OsSWEET2b in each of these membrane constructs. In comparison to previous OsSWEET2b simulations performed in a pure POPC bilayer, we confirm that simulations performed within a native-like membrane composition alter the stabilization of apo OsSWEET2b conformational states by ∼1 kcal/mol. The free-energy barriers of intermediate conformational states decrease when realistic membrane complexity is simplified, albeit roughly within sampling error, suggesting that protein-specific responses to membranes differ due to altered packing caused by compositional fluctuations. This work serves as a case study where a more realistic bilayer composition makes unbiased conformational sampling easier to achieve than with simplified bilayers.
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