Uncovering the mechanisms of cyclic peptide self-assembly in membranes with the chirality-aware MA(R/S)TINI forcefield.

Cyclic peptides (CPs) formed by alternation of D- and L-amino acids (D,L-CPs) can self-assemble into nanotubes (SCPNs) by parallel or/and antiparallel stacking. Different applications have been attributed to these nanotubes, including the disruption of lipid bilayers of specific compositions and the selective transport of ions throughout membranes. Molecular dynamics (MD) simulations have significantly contributed to understand the interaction between CPs, including the structural, dynamic and transport properties of their supramolecular aggregates. The high computational cost of atomic resolution forcefields makes them impractical for simulating the self-assembly of macromolecules, so coarse-grained (CG) models might represent a more feasible solution for this purpose. However, general CG models used for the simulation of biomolecules such as the MARTINI forcefield do not explicitly consider the non-covalent interactions leading to the formation of secondary structure patterns in proteins. This becomes particularly important in the case of CPs due to the D- and L-chirality alternation in their sequence, leading to opposite orientations of the backbone polar groups on both sides of the cyclic ring plane. In order to overcome this limitation, we have extended the MARTINI forcefield to introduce chirality in each residue of the CPs. The new parametrization, which we have called MA(R/S)TINI, reproduces the expected self-assembly patterns for several CP sequences in the presence of different membrane models, explicitly considering the chirality of the CPs and with no significant extra computational cost. Our simulations provide new mechanistic information of how these systems self-assemble in presence of different lipid scenarios, showing that the CP-CP and CP-membrane interactions are sensitive to the peptide sequence chirality. This opens the door to design new bioactive CPs based on CG-MD simulations. A web-based tool for the automatic parameterization of new CP sequences using MA(R/S)TINI, among other functionalities, is under construction (see http://cyclopep.com).