Studies on the Structure and Stability of Cyclic Peptide Based Nanotubes Using Oligomeric Approach: A Computational Chemistry Investigation

Abstract

In this study, an attempt has been made to investigate the structure, dynamics, and stability of cyclic peptide nanotubes (CPNTs) formed by the self-assembly of cyclic peptides (CPs) using classical molecular dynamics (MD) simulation and semiempirical quantum chemistry calculation employing PM6 Hamiltonian with the dispersion correction and hydrogen-bonding interaction (DH2). The structure and energetics of monomer and various oligomeric CPNTs have been investigated by considering the (cyclo-[(D-Ala-L-Ala)(4)]) peptide as the model for CP. Although the formation of CPNTs has been intensively studied, the present study adds valuable information to the de novo design of CPNTs. Various geometrical parameters extracted from the MD simulation reveal that the terminal residues are loosely hydrogen bonded to the inner subunits regardless of degree of oligomerization. The hydrogen bonds present in the inner core regions are stronger than the terminal residues. As the degree of oligomerization increases, the stability of the tube increases due to the hydrogen-bonding and stacking interactions between the subunits. The results show that the binding free energy increases with the extent of oligomerization and reaches saturation beyond pentamer CPNT. In addition, hydrophobic and electrostatic interactions play crucial roles in the formation of CPNTs. Analysis of both structure and energetics of the formation of CPNTs unveils that the self-assembly of dimer, trimer, and tetramer CPNTs are the essential steps in the growth of CPNTs.

Theoretical studies on the transport mechanism of 5-fluorouracil through cyclic peptide based nanotubes

“…26 However, the conformational entropy was not included due to the wide sampling space. The van der Waals (ΔE vdW ) and electrostatic (ΔE ele ) contributions to ΔG binding are presented in …”

Structure and stability of cyclic peptide based nanotubes: a molecular dynamics study of the influence of amino acid composition

“…In case of the AA system, the calculated energy components agree with the previous MD study. 27 It is evident from the results that the van der Waals contribution …”

“…The calculated average diameter for the AA system is 9.77 ' which is comparable with the results of a previous MD study. 27 The increase in the average diameters of the other CPNTs ranges from 0.2 to 0.7 '. It can be noted from these results that the incorporation of other amino acids slightly increases the average diameter of the CPNT when compared to the AA system.…”

“…27,44,45 The free energy of binding was averaged from 200 snapshots extracted from the last 2 ns production simulation with a 10 ps step size. The explicit water molecules were removed from each snapshot, and the free energy of binding of each CP unit with other CP units of the same system was calculated using…”

“…In the presence of bulky side chains, the backbone carbonyl-amide groups of CP are less exposed to the solvent medium from the tube surface. 27 The self-assembled…”