Broad commercialization and increasing resolving power of ion mobility spectrometry/mass spectrometry (IMS/MS) platforms have engendered an explosion of IMS applications to structural characterization of gas-phase biomolecules. That has renewed interest in more accurate and rapid ion mobility calculations that are needed to elicit ion geometries from the measurements. An approach based on scattering on electron density isosurfaces (SEDI) that mirrors the physics of molecular collisions was proven superior to the common methods involving atomic coordinates a decade ago but has remained impractical for large ions because of extreme computational demands. Here, we accelerate SEDI by up to ∼500 times using the fragment molecular orbital approach for surface generation and the multiplexed scattering algorithm in conjunction with the new grid extrapolation procedure for cross section evaluations. Parallelization of the code on a supercomputer has produced major further speed gains, allowing SEDI calculations for proteins (defined by over a million surface points) with a precision of <0.1% in 1 min. Initial tests reveal the anticipated dependence of mobility on the ion charge state and lower cross sections in view of reduced surface roughness. Present developments are expected to lead to broad application of SEDI in IMS studies of macromolecules, enabling more accurate and reliable structural assignments.