Abstract
The interactions between chiral molecules and cell membranes have attracted more and more attention in recent decades, due to their importance in molecular science and medical applications. It is observed that some peptides composed of different chiral amino acids may have distinct interactions with a membrane. How does the membrane exhibit a selective behavior related to the chirality of the peptides? Microscopically, the interactions between the peptides and the membrane are poorly understood. In this work, we study the interactions between an amphipathic peptide (C6) and POPC membrane with simulations. The kinetics and thermodynamics of peptide enantiomers during the adsorption to the membrane are characterized with direct simulations and umbrella sampling. It is observed that there are slow kinetics for the peptide composed of D-type amino acids. Along the observed pathways, the free energy landscapes are determined with umbrella sampling techniques. A free-energy barrier for the peptide composed of D-amino acids is observed, which is consistent with the kinetic observations. The results indicate the concurrent adsorption and rotation of the peptide helix. The local interactions between the peptides and the membrane are examined in detail, including the contact interactions between the peptides and the membrane, and the distributions of the lipids around the peptide. There are observable differences of the local interactions for the cases related to different peptide enantiomers. These results further demonstrate the importance of the rotation of peptide helix during the adsorption. More interestingly, all these kinetic differences between peptide enantiomers can be explained based on the conformations of the residue Trp and interactions between Trp and lipid molecules. These results give us a molecular understanding of the mechanism of the chirality-dependent peptide–membrane interactions, and may provide clues to designing systems which are sensitive to the chirality of membranes.
Highlights
Chirality is a property of many multi-atom molecules whose mirror objects are different from themselves
Peptide C6 is an analogue to cationic α-helical antimicrobial peptides (AMPs). It adopts a helical structure with amphipathic feature, with the charged and the hydrophobic residues distributed on two sides of the helix
Neutralizing ions are added to all systems. This kind of force field has been used in the simulations for α-helical AMPs [49,52] and POPC membranes [59], and the results showed good agreements with the experiments, which implies the important balance of force field parameters for proteins and lipids [49]
Summary
Chirality is a property of many multi-atom molecules whose mirror objects are different from themselves. Emergence of chirality is often attributed to the presence of asymmetric carbon atoms, as those in chiral amino acids and lipids as well as the proteins and membranes which are composed of the chiral units. This kind of local asymmetry produces different geometries of the molecules, and affect the interactions and functions between the chiral molecules. Variation in the chirality of the molecules would weaken or destroy their functions. To understand the role of chirality in molecular interactions is one of many important topics in molecular science [4]
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