Interactions between Membranes and “Metaphilic” Polypeptide Architectures with Diverse Side-Chain Populations

Abstract

At physiological conditions, most proteins or peptides can fold into relatively stable structures that present on their molecular surfaces specific chemical patterns partially smeared out by thermal fluctuations. These nanoscopically defined patterns of charge, hydrogen bonding, and/or hydrophobicity, along with their elasticity and shape stability (folded proteins have Young's moduli of ∼1 × 10 Pa), largely determine and limit the interactions of these molecules, such as molecular recognition and allosteric regulation. In this work, we show that the membrane-permeating activity of antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) can be significantly enhanced using prototypical peptides with "molten" surfaces: metaphilic peptides with quasi-liquid surfaces and adaptable shapes. These metaphilic peptides have a bottlebrush-like architecture consisting of a rigid helical core decorated with mobile side chains that are terminated by cationic or hydrophobic groups. Computer simulations show that these flexible side chains can undergo significant rearrangement in response to different environments, giving rise to adaptable surface chemistry of the peptide. This quality makes it possible to control their hydrophobicity over a broad range while maintaining water solubility, unlike many AMPs and CPPs. Thus, we are able to show how the activity of these peptides is amplified by hydrophobicity and cationic charge, and rationalize these results using a quantitative mean-field theory. Computer simulations show that the shape-changing properties of the peptides and the resultant adaptive presentation of chemistry play a key enabling role in their interactions with membranes.

Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1

“…Many antimicrobial peptides are thought to destabilize phospholipid bilayers by inducing NGC, a topological feature of membrane pores and blebs 19,[28][29][30][31][32][33][34] . Previously, we developed a machinelearning support vector machine (SVM) classifier trained to identify α-helical peptide sequences with the ability to remodel membranes by generating negative Gaussian curvature 18 .…”

“…Liposomes were prepared for SAXS experiments as previously described 19,34 . In brief, lyophilized phospholipids DOPG (…”

“…Methods used for SAXS experiments and data fitting were based around those that have been previously described 30,[33][34]55 .…”

Associative and Dissociative Processes in Non‐Covalent Polymer‐Mediated Intracellular Protein Delivery

“…Moving beyond CPPs, CPPMs and CPP‐inspired arginine‐rich helical peptides have also been studied in their capacity to interact with lipid membranes . The field of CPP–membrane interactions has also extended to include reports concerning TAT‐conjugated NPs, such as poly( l ‐lactide) and quantum dots, and how their membrane‐binding abilities correlate with their cellular uptake (Figure ) .…”

“…[79] Moving beyondC PPs, CPPMsa nd CPP-inspireda rginine-rich helical peptides have also been studied in their capacity to interact with lipid membranes. [80,81] The field of CPP-membrane interactions has also extended to include reports concerning TAT-conjugated NPs, such as poly(l-lactide) and quantum dots, and how their membrane-binding abilitiesc orrelate with their cellularu ptake (Figure 15). [82,83] However,i na nother case, NP-membrane bindingw as enhanced by using pyrene butyrate counteranions for TAT-functionalized quantum dots, but delivery was not improved.…”