Tryptophan, more than just an interfacial amino acid in the membrane activity of cationic cell-penetrating and antimicrobial peptides

Abstract

Trp is unique among the amino acids since it is involved in many different types of noncovalent interactions such as electrostatic and hydrophobic ones, but also in π-π, π-cation, π-anion and π-ion pair interactions. In membranotropic peptides and proteins, Trp locates preferentially at the water-membrane interface. In antimicrobial or cell-penetrating peptides (AMPs and CPPs respectively), Trp is well-known for its strong role in the capacity of these peptides to interact and affect the membrane organisation of both bacteria and animal cells at the level of the lipid bilayer. This essential amino acid can however be involved in other types of interactions, not only with lipids, but also with other membrane partners, that are crucial to understand the functional roles of membranotropic peptides. This review is focused on this latter less known role of Trp and describes in details, both in qualitative and quantitative ways: (i) the physico-chemical properties of Trp; (ii) its effect in CPP internalisation; (iii) its importance in AMP activity; (iv) its role in the interaction of AMPs with glycoconjugates or lipids in bacteria membranes and the consequences on the activity of the peptides; (v) its role in the interaction of CPPs with negatively charged polysaccharides or lipids of animal membranes and the consequences on the activity of the peptides. We intend to bring highlights of the physico-chemical properties of Trp and describe its extensive possibilities of interactions, not only at the well-known level of the lipid bilayer, but with other less considered cell membrane components, such as carbohydrates and the extracellular matrix. The focus on these interactions will allow the reader to reevaluate reported studies. Altogether, our review gathers dedicated studies to show how unique are Trp properties, which should be taken into account to design future membranotropic peptides with expected antimicrobial or cell-penetrating activity.

Cell-Penetrating Dabcyl-Containing Tetraarginines with Backbone Aromatics as Uptake Enhancers

“…Replacement of proline (Pro) with tryptophan (Trp) resulted in increased uptake of Tat48-60 [ 20 ], while replacing Trp with Leucine (Leu) diminished the uptake [ 21 ]. As Trp positively affects the uptake of CPPs, its role has been extensively studied, especially its position and quantity within a sequence [ 10 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

Tertiary Plasticity Drives the Efficiency of Enterocin 7B Interactions with Lipid Membranes

“…In fact, tryptophan may play an important role in interactions with the bacterial lipid bilayers and other membrane components. 29 Pore formation may be in fact primarily driven by surface tension exerted on the membrane by the peptide 30 or be proton motive force driven. 31 Enterocins 7A and 7B are a Class II (subclass IIb) enterocin pair that are produced by the Gram-stain positive bacterium Enterococcus faecalis 710C.…”

“…Disruption of Gram-stain positive membranes is a more difficult process due to the existence of a peptidoglycan cell wall , and may involve other features that are normally associated with bacteriocin activity being critical: the degree of cationic character, surface hydrophobicity, and the position of amphiphilic helices. In fact, tryptophan may play an important role in interactions with the bacterial lipid bilayers and other membrane components . Pore formation may be in fact primarily driven by surface tension exerted on the membrane by the peptide or be proton motive force driven …”

Orthogonal translation with 5‐cyanotryptophan as an infrared probe for local structural information, electrostatics, and hydrogen bonding

“…The unique biophysical properties of Trp allow its involvement in numerous interactions in proteins such as π-π stacking, hydrogen bonding, cation, and van der Waals packing interactions (Budisa & Paramita Pal, 2004). Its high fluorescence quantum yield and large molar extinction coefficient for transitions to excited states enable spectral studies with highly diluted sample solutions (Khemaissa et al, 2022). Trp fluorescence, particularly its emission wavelength, serves as a crucial indicator of the measurable physicochemical characteristics within its microenvironment.…”