(384f) Enhanced Sampling Methods for Structural Refinement of Proteins and Nucleic Acids

Flexible-fitting computational algorithms are often useful in the
interpretation of low-resolution electron microscopy (EM) data on
macromolecular assemblies. Molecular dynamics flexible fitting (MDFF)
is a widely used atomistic simulation technique to generate structural
models of such biomolecular complexes. All-atom explicit-solvent MDFF simulations
are not only computationally demanding, but also can be sensitive to
the resolution of the target EM map. Moreover, functional movements of
many biomolecules require large-scale conformational reorganization
elicited via domain translations/rotations, where methods such as MDFF
may be limited in capturing the rotations of structural
elements. Therefore, novel enhanced sampling methodologies need to be
integrated with MDFF to accelerate the conformational search in a
single atomistic simulation. Such strategies have the potential to
decrease the computational cost and alleviate the limitations stemming
from conformational reorganization. In this work, we judiciously
combine MDFF with temperature-accelerated molecular dynamics (TAMD),
an enhanced sampling method, and carry out TAMD-assisted MDFF (TAMDFF)
simulations of proteins and nucleic acids. We find that TAMDFF
simulations can achieve target structures of similar quality as MDFF
on shorter timescales. In some cases, only TAMDFF simulations are able
to capture conformational changes likely because MDFF simulations are
unable to overcome the underlying free-energy barriers. We suggest
that TAMDFF may be a viable strategy for structural refinement of
proteins, nucleic acids, and large ribonucleoprotein complexes such as
the ribosome.