Juan R. Perilla, Gongpu Zhao, Manman Lu, Jiying Ning, Guangjin Hou, In-Ja L.
Byeon, Angela M. Gronenborn, Tatyana Polenova, and Peijun Zhang.
CryoEM structure refinement by integrating NMR chemical shifts
with molecular dynamics simulations.
Journal of Physical Chemistry B, 121:3853-3863, 2017.
(PMC: PMC5459578)
PERI2017-JRP
Single particle cryoEM has emerged as a powerful method for structure
determination of proteins and complexes, complementing X-ray
crystallography and NMR spectroscopy. Yet, for many systems, the
resolution of cryoEM density map has been limited to 4-6 Å, which only
allows for resolving bulky amino acids side chains, thus hindering accurate
model building from the density map. On the other hand, experimental
chemical shifts (CS) from solution and solid state MAS NMR spectra
provide atomic level data for each amino acid within a molecule or a
complex; however, structure determination of large complexes and
assemblies based on NMR data alone remains challenging. Here, we
present a novel integrated strategy to combine the highly complementary
experimental data from cryoEM and NMR computationally by molecular
dynamics simulations to derive an atomistic model, which is not attainable
by either approach alone. We use the HIV-1 capsid protein (CA) C-terminal
domain as well as the large capsid assembly to demonstrate the feasibility
of this approach, termed NMR CS-biased cryoEM structure refinement.
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