Simulations of amphiphilic peptide assembly at the air-water interface

Amphiphilic peptides, Pro-Glu-(Phe-Glu)n-Pro, Pro-Asp-(Phe-Asp)n-Pro, and Phe-Glu(Phe-Glu)n-Phe, composed of n recurring sequences of alternating hydrophobic and hydrophilic amino acids can be designed such that they self-assemble into monolayers at the air-water interface. In biomimetic systems, these provide template matrices at the organic-aqueous interface to promote crystallization of hydroxyapatite, which can serve as a treatment for osteoporosis. In this work, computer simulations have been employed to investigate the structure and interactions which govern peptide self-assembly on the microscopic level. Atomistic molecular dynamics simulations of single peptide strands show that they readily align at the air-water interface and have the ability to fold into β-hairpins, even for fairly short peptide lengths (n = 2). Such rare events (i.e. conformational changes) require the use of advanced sampling techniques. Here, replica exchange molecular dynamics has been used to study the conformational preferences of different peptide sequences. Simulation results revealed that peptides with shorter acidic side-chains (Asp vs. Glu) exhibit more extended conformations than those with longer side-chains which could reach the proline termini. Furthermore, studies suggest that the proline termini (Pro vs. Phe) are necessary to preserve the 2D order within the monolayer aggregates, as has been observed experimentally. The peptide Pro-Asp-(Phe-Asp)nPro, which contains both of these features, shows the most ordered assembly, only a small twist in the backbone, and is able to stabilize the formed aggregates via hydrogen-bonding between acidic side-chains, making it the most suitable candidate for self-assembly. This has also been supported by assessing the stability of pre-assembled peptide aggregates as well as their tendency to self-assemble from initially disordered configurations. As atomistic simulations are limited to small system sizes and relatively short simulation times, a coarse-grained model is developed to be able to study the self-assembly on a larger scale. Since self-assembly at the interface is of interest, existing coarse-graining (CG) methodology has been expanded to determine non-bonded potentials for inhomogeneous systems. The developed method is analogous to iterative Boltzmann inversion but constructs the update for the interaction potential based on the radial distribution function calculated in a slab geometry and the slab and interfacial widths, which allows a balance between the local liquid structure and the thermodynamic properties of the interface. The new method has been demonstrated for slabs of liquid water and methanol in vacuum, as well as a solute-solvent system of a single benzene molecule at the vacuum-water interface, which is of particular importance in biology, where the thermodynamic/interfacial behavior often needs to be included in addition to the structural properties of the system. Based on this, a CG model for the system was parametrized via a fragment-based approach and the peptide’s affinity for the air-water interface has been tested. Although its individual fragments reproduced both the structure as well as the probability distributions to stay at the interface, the peptide as a whole diffused into the bulk. However, a reparametrization of the non-bonded interaction for one of the backbone beads in a trimer lead the CG peptide to remain at the interface. This indicates that the chain’s connectivity plays an important role on the peptide’s behavior at the interface.