Efficient sampling of large-scale transition pathways and intermediate conformations in sub-mesoscopic protein...

Protein conformational changes are the cornerstone of biological function. While conformers captured experimentally represent metastable states, the pathways connecting them have been elusive for experiments and simulations alike. Nowadays, cryogenic Electron Microscopy is providing rich structural data on proteins trapped in different states for increasingly large systems, but these are out of scope for most computational methods which exhibit an N² dependence on size. Based on our previous eBDIMS algorithm, here we present eBDIMS2, an optimized version with quasi-linear size dependence, able to simulate on a desktop computer particularly complex transitions for megadalton protein assemblies, like the rotary motion of ATP synthases. Not only eBDIMS2 pathways spontaneously visit experimental intermediates but also overlap with enhanced and microsecond Molecular Dynamics simulations requiring extensive supercomputing resources. By integrating Elastic Networks with Brownian Dynamics, eBDIMS2 allows an unprecedented exploration of conformational changes of sub-mesoscopic systems previously inaccessible.