Comparison of pathways from the geometric targeting method and targeted molecular dynamics in nitrogen regulatory...

Geometric targeting (GT) is a recently introduced method for rapidly generating all-atom pathways from one protein state to another, based on geometric rather than energetic considerations. To generate pathways, a bias is applied that gradually moves atoms toward a target structure, while a set of geometric constraints between atoms is enforced to keep the structure stereochemically acceptable. In this work, we compare conformational pathways generated from GT to pathways from the much more computationally intensive and commonly used targeted molecular dynamics (TMD) technique, for a complicated conformational change in the signaling protein nitrogen regulatory protein C. We show that the all-atom pathways from GT are similar to previously reported TMD pathways for this protein, by comparing motion along six progress variables that describe the various structural changes. The results suggest that for nitrogen regulatory protein C, finding an all-atom pathway is primarily a problem of geometry, and that a detailed force field in this case constitutes an unnecessary extra layer of detail. We also show that the pathway snapshots from GT have good structure quality, by measuring various structure quality metrics. Transient hydrogen bonds detected by the two methods show some similarities but also some differences. The results justify the usage of GT as a rapid, approximate alternative to TMD for generating stereochemically acceptable all-atom pathways in highly constrained protein systems.