Cationic membrane peptides: atomic-level insight of structure–activity relationships from solid-state NMR

Abstract

Many membrane-active peptides, such as cationic cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs), conduct their biological functions by interacting with the cell membrane. The interactions of charged residues with lipids and water facilitate membrane insertion, translocation or disruption of these highly hydrophobic species. In this mini-review we will summarize high-resolution structural and dynamic findings towards the understanding of the structure-activity relationship of lipid membrane-bound CPPs and AMPs, as examples of the current development of solid-state NMR (SSNMR) techniques for studying membrane peptides. We will present the most recent atomic-resolution structure of the guanidinium-phosphate complex, as constrained from experimentally measured site-specific distances. These SSNMR results will be valuable specifically for understanding the intracellular translocation pathway of CPPs and antimicrobial mechanism of AMPs, and more generally broaden our insight into how cationic macromolecules interact with and cross the lipid membrane.

Magic Angle Spinning NMR of Proteins: High-Frequency Dynamic Nuclear Polarization and 1H Detection

“…For example, membrane proteins usually have a certain topology, defined as insertion depth and orientation. They interact with lipid through charge-charge or hydrophobic interactions (20,30). Moreover, the impact of protein on the lipid membrane can be functionally relevant.…”

Cardiolipin interaction with subunit c of ATP synthase: Solid-state NMR characterization

“…These methods have been used to study several systems of highly relevant biological interest. One can quote for example the mechanism by which a virus merges with cell membranes [33], the action of antimicrobial peptides [34], and the implication of lipids in the mechanism of membrane proteins, such as the regulator cardiac muscle Phospholamban [35,36], or the potassium channel KcsA [37,38]. Implication of these interactions in non-viral pathologies, such as Huntingtin disease [39] or blood clotting [40], has also been investigated.…”

Enhancing cellular uptake of GFP via unfolded supercharged protein tags

“…Arg7 and Arg9 have been used in vivo for the transfer of cyclosporine [12] and human catalase [13], respectively. Several experimental and theoretical studies were carried out to elucidate the mechanism for translocation of CPPs and to investigate the role of different positively charged amino acid residues [14,15]. However, it was also demonstrated that polycations can induce toxicity such as mitochondria-mediated apoptosis [16].…”