Tracing Conformational Changes in Proteins Represented at a Coarse Level

Abstract

Many large protein complexes undergo extensive conformational changes as part of their functionality. Tracing these changes is important for understanding the way these proteins function. It is not always possible to obtain a high resolution structure for very large complexes. Electron cryo-microscopy (Cryo-EM) enables the representation of large macromolecular structures at a medium resolution level (4–8A). Traditional conformational search methods cannot be applied to medium resolution data where structural information may be partial or missing. Additionally, simulating large scale conformational changes in proteins require a massive amount of computational efforts. We apply a search method from robotics to structural information obtained from medium resolution Cryo-EM maps, modeled to approximate backbone trace level. The pathways obtained by this method can be useful in understanding protein motions, providing reliable results for the medium resolution data. To provide a baseline validation for our method, we tested it on Adenylate Kinase and Cyanovirin. To test the data on actual cryo-EM determined structures, we simulated the conformational opening of the GroEL single ring complex. We show that we can produce low energy conformational pathways which correspond to known structural data. The method presented here is a promising step towards exploring the conformational motion of even larger complexes.