Electron cryo-microscope (cryo-EM) becomes one of the most essential experimental tools to determine structures of large macromolecular complexes. The resolution of structures observed by the cryo-EM is usually lower than X-ray crystallography, and thereby, modeling of atomic structures based on the cryo-EM images is still an important subject of computational biophysics. A flexible fitting approach has often been applied for the modeling, when one or a few known experimental structures are available for target macromolecules.<br/>We recently developed an efficient flexible fitting method combining extensive parallelization, multi-scale models, and enhanced conformational sampling and introduced it in the GENESIS MD software package. In the new method, not only molecular mechanics computations but also biased energy/force computations based on the correlation coefficients (c.c.) are parallelized. This parallelization enables efficient calculations of the flexible fittings to cryo-EM images and allows the usage of fully atomistic models with explicit solvents/membranes in the final stages of the calculations. Enhanced conformational sampling methods, such as simulated annealing, replica-exchange molecular dynamics, or replica-exchange umbrella sampling, are available in the flexible fitting calculations using the Cα-Go model, all-atom Go model, all-atom force-field models with implicit/explicit solvents. The method contributes to higher resolution structural modeling from cryo-EM images and connects the flexible fitting calculations to the molecular dynamics simulations for investigating the structure-dynamics-function relationships of target macromolecules.

Development of the flexible-fitting MD simulation method for cryo-EM images of large macromolecular structures and dynamics

256th National Meeting (2018)

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