Structure and Stability of Cyclic Peptide Based Nanotubes: An Molecular Dynamics Study of the Influence of Amino Acid Composition

The stability of self-assembling cyclic peptides (CPs) is attained by the intermolecular backbone-backbone hydrogen bonding (H-bonding) interactions. In addition to this Hbonding interaction, the self-assembled CPs are further stabilized by various intermolecular side chain-side chain interactions. This study investigates the role of amino acids on the structure and stability of self-assembled CPs using classical molecular dynamics (MD) simulations and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The amino acids considered for the construction of model structures of cyclic peptide nanotubes (CPNTs) are Ala, Leu, Phe, Gln, Glu, and Trp. The calculated structural parameters from classical MD simulation reveal that the backbone flexibility of CPNTs composed of non-Ala residues is an intrinsic property of the amino acids. The presence of an Ala residue at the alternate position increases the solvation of side chains of Gln residue. The occurrence of Glu residue does not favour the formation of intermolecular side chain-side chain H-bonding interaction in aqueous medium. It is evident from the calculated free energy of binding that the CPNTs composed of non-polar residues are highly stable in aqueous medium. At the same time, the CPNTs with polar side chains are less stable in aqueous medium. Results obtained from this study demonstrate the role played by amino acid side chains on the structure and stability of CPNTs and provide valuable suggestions on the design of CPNTs with moderate stability in various solvent environments.