Design of Peptides for Membrane Insertion: The Critical Role of Charge Separation.
J Phys Chem B
; 126(34): 6454-6463, 2022 09 01.
Article
en En
| MEDLINE
| ID: mdl-35997537
ABSTRACT
A physical understanding of membrane permeation and translocation by small, positively charged molecules can illuminate cell penetrating peptide mechanisms of entry and inform drug design. We have previously investigated the permeation of the doubly charged peptide WKW and proposed a defect-assisted permeation mechanism where a small molecule with +2 charge can achieve a metastable state spanning the bilayer by forming a membrane defect with charges stabilized by phospholipid phosphate groups. Here, we investigate the membrane permeation of two doubly charged peptides, WWK and WWWK, with charges separated by different lengths. Through complementary experiments and molecular dynamics simulations, we show that membrane permeation was an order of magnitude more favorable when charges were separated by an â¼2-3 Å greater distance on WWWK compared to WWK. These results agree with the previously proposed defect-assisted permeation mechanism, where a greater distance between positive charges would require a less extreme membrane defect to stabilize the membrane-spanning metastable state. We discuss the implications of these results in understanding the membrane permeation of cell-penetrating peptides and other small, positively charged membrane permeants.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos de Penetración Celular
/
Membrana Dobles de Lípidos
Idioma:
En
Revista:
J Phys Chem B
Asunto de la revista:
QUIMICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos