Sequence Patterning Governs Lipid-Selective Insertion and Membrane Perturbation of Antimicrobial Peptoids

Area of Science:

• Biochemistry and Biophysics
• Molecular Dynamics
• Materials Science

Background:

• Peptoids (poly-N-substituted glycines) are stable, protease-resistant peptidomimetics with tunable amphiphilicity.
• Understanding peptoid-lipid interactions is crucial for developing effective membrane-active agents.
• The precise molecular determinants of lipid selectivity in peptoids are not fully understood.

Purpose of the Study:

• To investigate how alternating and diblock antimicrobial peptoid sequences interact with model bacterial membranes.
• To characterize sequence- and composition-dependent peptoid behavior at the molecular level.
• To elucidate the relationship between peptoid sequence, lipid composition, and membrane activity.

Main Methods:

• Extensive all-atom molecular dynamics simulations were performed.
• Quantified insertion depth, residue-lipid contacts, and bilayer structural responses.
• Utilized correlation analysis and principal component analysis to identify key molecular drivers.

Main Results:

• Peptoid insertion depth is strongly dependent on lipid composition and amphiphilic organization.
• Increased anionic lipid content promotes deeper peptoid insertion.
• Alternating sequences lead to uniform hydrophobic contacts, while diblock architectures cause localized membrane perturbations.
• Residue-lipid contact density is the primary factor influencing insertion depth, not global compactness.
• Deeper insertion correlates with localized reductions in membrane thickness.

Conclusions:

• Sequence patterning and lipid composition significantly influence antimicrobial peptoid membrane interactions.
• Lipid-selective insertion is driven by contact-based penetration and local bilayer responses.
• These findings clarify the molecular basis of lipid-selective insertion in sequence-defined peptidomimetics.