Network Hamiltonian models (NHMs) are a framework for
topological
coarse-graining of protein–protein interactions, in which each
node corresponds to a protein, and edges are drawn between nodes representing
proteins that are noncovalently bound. Here, this framework is applied
to aggregates of γD-crystallin, a structural protein of the
eye lens implicated in cataract disease. The NHMs in this study are
generated from atomistic simulations of equilibrium distributions
of wild-type and the cataract-causing variant W42R in solution, performed
by Wong, E. K.; Prytkova, V.; Freites, J. A.; Butts, C. T.; Tobias,
D. J. Molecular Mechanism of Aggregation of the Cataract-Related γD-Crystallin
W42R Variant from Multiscale Atomistic Simulations. Biochemistry
2019, 58 (35), 3691–3699.
Network models are shown to successfully reproduce the aggregate size
and structure observed in the atomistic simulation, and provide information
about the transient protein–protein interactions therein. The
system size is scaled from the original 375 monomers to a system of
10000 monomers, revealing a lowering of the upper tail of the aggregate
size distribution of the W42R variant. Extrapolation to higher and
lower concentrations is also performed. These results provide an example
of the utility of NHMs for coarse-grained simulation of protein systems,
as well as their ability to scale to large system sizes and high concentrations,
reducing computational costs while retaining topological information
about the system.