Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

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.

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