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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
103
68-POS
Board 28
Multiscale Enhanced Sampling for Glucokinase
Kei Moritsugu
1
, Tohru Terada
2
, Akinori Kidera
1
.
1
Yokohama City University, Yokohama, Japan,
2
The University of Tokyo, Tokyo, Japan.
Free energy landscapes derived from all-atom protein conformational ensembles have played an
important role for elucidating protein functional dynamics with high structural and energetic
resolution. Since the characteristic time scale of biologically relevant processes such as protein
structural changes far exceeds the feasible computational time, the calculations of protein free
energy landscapes require the acceleration of conformational samplings and mapping along the
reaction coordinates or the pathways of such structural changes. Here, a multiscale molecular
dynamics simulation method, “multiscale essential sampling (MSES)”, has been proposed which
enables full conformational samplings of large proteins at atomic resolution including explicit
solvent. In MSES, the sampling of a full-dimensional model is enhanced by coupling with
accelerated dynamics of the associated coarse-grained model (CG), together with a multicopy
scheme, Hamiltonian replica exchange, to remove the biasing potential in MSES. CG is then
useful for determining the sampling region according to our purpose, and can be suitably defined
by prior knowledge such as experimental data.
MSES has been further extended for maximizing the CG driving force and applied to large
systems in solution such as intrinsically disordered protein, protein complex, and protein-ligand
interaction. Here, a recent application has been presented to glucokinase, an enzyme that
facilitates phosphorylation of glucose for the regulation of carbohydrate metabolism.
Conformational ensembles of glucokinase with and without bound glucose were fully calculated
by MSES and found to be extended ranging from closed to open and super-open structures,
which is consistent with the previous SAXS experiments. The result clarified the structural basis
of positive cooperativity for the activity of glucokinase in response to glucose concentration that
originates from a high energy barrier between the closed and open structures relating to the
helix-coil transition of an interfacial helix.