Yuhang Wang, Mrinal Shekhar, Darren Thifault, Christopher J Williams, Ryan
Mcgreevy, Jane Richardson, Abhishek Singharoy, and Emad Tajkhorshid.
Constructing atomic structural models into cryo-EM densities using
molecular dynamics - pros and cons.
Journal of Structural Biology, 204:319-328, 2018.
(PMC: PMC6394829)
WANG2018-ET
Accurate structure determination from electron density maps at 3-5
resolution necessitates a balance between extensive global and local
sampling of atomistic models, yet with stereochemical correctness of
backbone and sidechain geometries. Molecular Dynamics Flexible Fitting
(MDFF), particularly through a resolution-exchange scheme, ReMDFF,
provides a robust way of achieving this balance for hybrid structure
determination. Employing two high-resolution density maps, namely that of
-galactosidase at 3.2 and TRPV1 at 3.4 , we showcase
the quality of ReMDFF-generated models, comparing them against ones
submitted by independent research groups for the 2015-2016 Cryo-EM
Model Challenge. This comparison offers a clear evaluation of ReMDFF’s
strengths and shortcomings, and those of data-guided real-space
refinements in general. ReMDFF results scored highly on the various metric
for judging the quality-of-fit and quality-of-model. However, some
systematic discrepancies are also noted employing a Molprobity analysis,
that are reproducible across multiple competition entries. A space of key
refinement parameters is explored within ReMDFF to observe their impact
within the final model. Choice of force field parameters and initial model
seem to have the most significant impact on ReMDFF model-quality. To this
end, very recently developed CHARMM36m force field parameters provide
now more refined ReMDFF models than the ones originally submitted to the
Cryo-EM challenge. Finally, a set of good-practices is prescribed for the
community to benefit from the MDFF developments.
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