Impact of arginine modified SNARE peptides on interactions with phospholipid bilayers and coiled-coil formation: A molecular dynamics study

• DOI: 10.1016/j.molliq.2022.119972
• Publication Date: 2022-08-04T05:51:37Z
• Authors: Bence Fehér; Levena Gascoigne; Sanne N. Giezen; Ilja K. Voets
• Keywords: SNARE; Membrane; Molecular dynamics; Fusion; Arginine; 01 natural sciences; 0104 chemical sciences

Membrane fusion plays a vital role in several biological processes such as cellular uptake, communication between cells and RNA delivery. Due to its complexity, model membranes and minimalistic fusion protein models are often used to gain insight into the fusion process. Coiled–coil (CC) peptides, consisting of two to five –helical peptides, are highly advantageous as minimalistic protein models. One of the most common fusion CC complex is formed between the complementary peptides E ((KIAALKE)4) and K ((EIAALEK)4). In this system, K peptides have been suggested to prime the membrane for fusion by causing small lipid protrusions within the membrane, increasing local curvature and membrane dehydration. In this study, we develop a library of peptides based on K peptide sequence by substituting lysine amino acids with arginine at varying heptad locations. By molecular dynamics simulations, we find that increasing the amount of arginine in the peptides results in enhanced affinity to the membrane. With coarse-grained simulations, we show that the interaction of peptides with the membrane triggers increased curvature in the membrane without significantly disrupting the lipid packing. Additionally, we find that all modified peptides retain the capability of forming CC complexes with E peptides. Our results suggest that arginine positioning is critical when designing CC fusion peptides. Peptides with arginines located at the N–terminus (ARG1, ARG6) show greater affinity to the lipid membrane. Our simulations suggest that introducing arginine into CC peptide sequences can enhance the binding affinity to the membrane via hydrogen bonds and may lead to more effective CC fusion peptides than E–K complexes.