Design of short peptides and peptide amphiphiles as collagen mimics and an investigation of their interactions with collagen using molecular dynamics simulations and docking studies

Short peptide sequences and bolaamphiphiles derived from natural proteins are gaining importance due to their ability to form unique nanoscale architectures for a variety of biological applications. In this work, we have designed six short peptides (triplet or monomeric forms) and two peptide bolaamphiphiles that either incorporate the bioactive collagen motif (Gly-X-Y) or sequences where Gly, Pro, or hydroxyproline (Hyp) are replaced by Ala or His. For the bolaamphiphiles, a malate moiety was used as the aliphatic linker for connecting His with Hyp to create collagen mimics. Stability of the assemblies was assessed through molecular dynamics simulations and results indicated that (Pro-Ala-His)(3) and (Ala-His-Hyp)(3) formed the most stable structures, while the amphiphiles and the monomers showed some disintegration over the course of the 200 ns simulation, though most regained structural integrity and formed fibrillar structures, and micelles by the end of the simulation, likely due to the formation of more thermodynamically stable conformations. Multiple replica simulations (REMD) were also conducted where the sequences were simulated at different temperatures. Our results showed excellent convergence in most cases compared to constant temperature molecular dynamics simulation. Furthermore, molecular docking and MD simulations of the sequences bound to collagen triple helix structure revealed that several of the sequences had a high binding affinity and formed stable complexes, particularly (Pro-Ala-His)(3) and (Ala-His-Hyp)(3). Thus, we have designed new hybrid-peptide-based sequences which may be developed for potential applications as biomaterials for tissue engineering or drug delivery.