Acceleration of cryo-EM Flexible Fitting for Large Biomolecular Systems by Efficient Space Partitioning

Flexible fitting is a powerful technique to build the 3D structures of biomolecules from cryoelectron microscopy (cryo-EM) density maps. One popular method is a cross-correlation coefficient-based approach, where the molecular dynamics (MD) simulation is carried out with the biasing potential that includes the cross-correlation coefficient between the experimental and simulated density maps. Here, we propose efficient parallelization schemes for the calculation of the cross-correlation coefficient to accelerate flexible fitting. Our schemes are tested for small, medium, and large biomolecules using CPU and hybrid CPU + GPU architectures. The scheme for the atomic decomposition MD is suitable for small proteins such as Ca²⁺-ATPase with the all-atom Go model, while that for the domain decomposition MD is better for larger systems such as ribosome with the all-atom Go or the all-atom explicit solvent models. Our methods allow flexible fitting for various biomolecules with reasonable computational cost. This approach also connects high-resolution structure refinements with investigation of protein structure-function relationship.