A New Mixed All-Atom/Coarse-Grained Model: Application to Melittin Aggregation in Aqueous Solution

[Image: see text] We introduce a new mixed resolution, all-atom/coarse-grained approach (AACG), for modeling peptides in aqueous solution and apply it to characterizing the aggregation of melittin. All of the atoms in peptidic components are represented, while a single site is used for each water molecule. With the full flexibility of the peptide retained, our AACG method achieves speedups by a factor of 3–4 for CPU time reduction and another factor of roughly 7 for diffusion. An Ewald treatment permits the inclusion of long-range electrostatic interactions. These characteristics fit well with the requirements for studying peptide association and aggregation, where the system sizes and time scales require considerable computational resources with all-atom models. In particular, AACG is well suited for biologics since changes in peptide shape and long-range electrostatics may play an important role. The application of AACG to melittin, a 26-residue peptide with a well-known propensity to aggregate in solution, serves as an initial demonstration of this technology for studying peptide aggregation. We observed the formation of melittin aggregates during our simulations and characterized the time-evolution of aggregate size distribution, buried surface areas, and residue contacts. Key interactions including π-cation and π-stacking involving TRP19 were also examined. Our AACG simulations demonstrated a clear salt effect and a moderate temperature effect on aggregation and support the molten globule model of melittin aggregates. As a showcase, this work illustrates the useful role for AACG in investigations of peptide aggregation and its potential to guide formulation and design of biologics.