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

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.