In this study, we employed all-atom molecular dynamics simulations to investigate the membrane interaction behaviors of two structurally distinct peptoid sequences each consisting of hydrophilic residue NLys (N-(4-aminobutyl) glycine, K) and hydrophobic residue Nspe (N-(s)-(1-phenethyl) glycine, Z). The first peptoid followed an alternating pattern (KZKZKZ) while the second adopted a diblock pattern (KKKZZZ). Simulations were conducted with three biologically relevant model membranes representing gram-positive bacteria, gram-negative bacteria and bacterial inner membrane to access the influence of lipid composition on peptoid behavior.
Key structural and interaction descriptors, including the number of contacts between peptoid and lipid residues, omega dihedral angle distributions, hydrogen bond formation, and radius of gyration, were analyzed, with particular emphasis on the insertion depth as a measure of membrane penetration. Correlation analyses were performed to examine the relationships between these structural and interaction descriptors and insertion depth, providing insights into the factors governing membrane interactions.
Our study highlights the critical role of peptoid sequence patterns in determining membrane insertion behavior. Our results demonstrate that the alternating peptoid sequence exhibits a more favorable insertion depth capacity compared to the diblock sequence across all membrane types except the gram-negative model. This enhanced insertion is attributed to a more uniform spatial distribution of hydrophobic and hydrophilic residues, promoting balanced interactions with both the membrane core and the polar headgroup regions. Furthermore, membrane composition was found to significantly influence insertion dynamics. These findings contribute to the fundamental understanding of sequence-dependent membrane interactions of peptoids and provide valuable insights for the rational design of peptoid-based antimicrobial agents.