A novel fast Fourier transform accelerated off-grid exhaustive search method for cryo-electron microscopy fitting

This paper presents a novel fast Fourier transform (FFT)-based exhaustive search method extended to off-grid translational and rotational degrees of freedom. The method combines the advantages of the FFT-based exhaustive search, which samples all the conformations of a system under study on a grid, with a local optimization technique that guarantees to find the nearest optimal off-grid conformation. The method is demonstrated on a fitting problem and can be readily applied to a docking problem. The algorithm first samples a scoring function on a six-dimensional grid of size N⁶ using the FFT. This operation has an asymptotic complexity of O(N⁶logN). Then, the method performs the off-grid search using a local quadratic approximation of the cost function and the trust-region optimization algorithm. The computation of the quadratic approximation is also accelerated by FFT at the same additional asymptotic cost of O(N⁶logN). The method is demonstrated by fitting atomic protein models into several simulated and experimental maps from cryo-electron microscopy. The method is available at https://team.inria.fr/nano-d/software/offgridfit.