Generating stereochemically acceptable protein pathways

Abstract

We describe a new method for rapidly generating stereochemically acceptable pathways in proteins. The method, called geometric targeting, is publicly available at the webserver http://pathways.asu.edu, and includes tools for visualization of the pathway and creating movie files for use in presentations. The user submits an initial structure and a target structure, and a pathway between the two input states is generated automatically. Besides visualization, the structural quality of the pathways makes them useful as input pathways into pathway refinement techniques and further computations. The approach in geometric targeting is to gradually change the system's RMSD relative to the target structure while enforcing a set of geometric constraints. The generated pathways are not minimum free energy pathways, but they are geometrically plausible pathways that maintain good covalent bond distances and angles, keep backbone dihedral angles in allowed Ramachandran regions, avoid eclipsed side-chain torsion angles, avoid non-bonded overlap, and maintain a set of hydrogen bonds and hydrophobic contacts. Resulting pathways for over 20 proteins featuring a wide variety of conformational changes are reported here, including the very large GroEL complex.