- This screening strategy is likely to work best where the cap-
tured conformation is less affected by the bound Fab/VHH
domain [178]. - CPMG data can be difficult to interpret; there are cases where
MD simulations found hidden conformations which in turn
enabled the understanding of CPMG data through the fitting
of a suitable model [179, 180]. - This is a particularly interesting study, as it uses an approach
which requires only a small amount of initial knowledge about
the transition. - An interesting recent study combines celling with a self-
seeding approach which uses the shape of the local energy
surface to guess at new conformations to start unbiased simu-
lations from [181] - Previous NMR studies offered limited but specific information
about which side-chains were involved in this allostery. How-
ever, this information is not sufficient to build a CV to correctly
sample these invisible states of KIX as the protein must access
an excited state seen on a timescale of ~3 ms. In this case a
special form of metadynamics, the well-tempered ensemble
(WTE), was applied and the potential energy was used as a
CVand biased. With the WTE the average energy is the same as
seen without bias but the fluctuations are amplified, and the
correct distribution can be generated through reweighting.
A WTE simulation was able to extensively sample the excited
state of KIX, in 100 ns of atomistic biased simulation, allowing
a detailed understanding of the allosteric mechanism previously
not possible.
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