Native H/D exchange kinetics predicted by structure based model simulations

CRAIG PO; LATZER J; WEINKAM P; HOFFMAN, RMB; KOMIVES EA; WOLYNES P

San Diego, CA, USA.

Congreso; 7th International Conference on Biological Physics.; 2011

Craig PO, Lätzer J, Weinkam P, Hoffman R, Komives E, Wolynes P

Simulations based on perfectly funnelled landscapes have been able to capture many of the fundamental aspects of protein folding. When frustration is low enough the topology becomes the main factor determining the folding process. In the most fundamental implementation of the minimal frustration principle only native interactions significantly contribute to the stabililization of the protein structure. Using these ideas and coarse grain models an extensive sampling of the energy landscape could be achieved. We explored the use of such models to interpret native state hydrogen/deuterium exchange of backbone amides (HDX) and whether they are able to give a quantitative description of the native protein ensembles. We developed a method for predicting the local stability of proteins simulated using perfectly funnelled structure based models, and show that these predictions compare favourably with experimental measurements of single residue HDX. The approach was applied to ubiquitin, cytochrome-C, HEWL, S6, and IkBalpha70-206. A variety of simulation models with homogeneous, heterogeneous, additive as well as non additive contact potentials were evaluated for their agreement with experiment. We also compare the results obtained using different criteria for structurally defining the open and closed states based on the number of native contacts of each residue, the dynamics of hydrogen bonded residues or a combination of both criteria.