Coarse-grained
modeling and simulations with YASARA
Experimental structure
determination depends on the availability of large numbers
of structurally identical copies that can be averaged,
either in an X-ray crystal, in an NMR solution, or on a
cryo-EM layer. On the mesoscale, where proteins, nucleic
acids, and lipids assemble to form enveloped viruses,
vesicles, bacterial cells, or eukaryotic cell
compartments, the inherent randomness of the assembly
processes makes sure that no two structures are the same.
Electron microscopic images show a large variety of sizes
and shapes, which preclude high-resolution structure
determination. Alternatively, molecular modeling can serve
as a route to fill these images with all-atom life, which
is needed to improve our structural understanding of these
large structures, to test hypotheses, to create starting
structures for simulation on supercomputers, or for
educational purposes.
YASARA
Dynamics and YASARA
Structure include the functionality to construct
such mesoscale models from modular building blocks and
visualize them using all common molecular graphics styles.
The model building process relies on an intermediate
coarse-grained "pet world" representation whenever
all-atom details would be computationally too costly. In
the pet world, molecules are scaled to 1/10th the normal
size and represented by pet atoms, which requires only 2%
of the original atom number (see Figure 2 on the right).
This allows for efficient collision detection to generate
tight packings as well as large-scale coarse-grained
molecular dynamics simulations, e.g. to pack a
hypothetical virus genome (see Figure 1 on the right).
Nucleic acids and entire genomes with binding proteins
can be built directly from a FASTA file, that can contain a
secondary structure assignment
in dot-bracket notation for single-stranded nucleic acids.
The model building procedure
is fully automated and employs a collection of open source
YASARA macros, which can easily be adapted to build your
own models. Coarse-grained pet proteins are mostly rigid
during a simulation, so that all proteins of a certain
type keep the same initial shape and can later be
visualized with identical instances of one single all-atom
model, yielding the data compression needed to handle gigastructures with billions
of atoms. So pet world simulations are not a faster replacement for all-atom simulations, but aimed at model building only.
An infrastructure for sharing
these macros and the generated mesoscale models has been
set up as the PetWorld Database, and you are welcome to
contribute your own models in exchange for free access to
all YASARA stages. Building mesoscale models is also a fun
task for molecular modeling courses, where each
participant takes care of modeling one of the proteins,
and then they join forces to assemble the complete model.
Detailed building instructions
and infos how to get YASARA for free in return for your
contribution can be found in the user manual of any YASARA
stage (including the free YASARA View) if you browse to Recipes
> Build a gigastructure.
R E F E R E
N C E S
[1] Assembly
of biomolecular gigastructures and visualization with
the Vulkan graphics API
Ozvoldik K, Stockner T, Rammner B, and Krieger E (2021).
Journal of Chemical Information and Modeling61,
5293-5303
Figure
1: The video above shows the
coarse-grained MD simulation of the packaging of
a hypothetical self-assembling viral
nucleocapsid (consisting of a nucleic acid
wrapped around a protein) into a budding
particle. The yellow sphere represents the
growing membrane. The movie is a time lapse, the
computation takes a few hours.
Figure 2: The
screenshot shows the transformation from an
all-atom model of the holiday junction (PDB ID
1XNS) with bound DNA to a coarse-grained pet model
(scaled up for comparability). Pet atoms are
colored by size from blue (0.2 Å) via magenta, red
orange, yellow, green to cyan (1.1 Å) and gray (1.2 Å). Since the
nucleic acid is partly single-stranded, the
coarse-grained model uses one red pet atom for
each nucleotide.
