Mechanical unfolding pathway and origin of mechanical stability of proteins of ubiquitin family: an investigation by steered molecular dynamics simulation.

Like the muscle protein Titin, proteins of the ubiquitin family exhibit a parallel strand arrangement, but otherwise having a distinctly different fold and not involved in an obvious load-bearing function, exhibit high resistance to mechanical unfolding. We have applied all-atom molecular dynamics simulation technique in implicit solvent to present a deep insight into the force-induced unfolding pathway of three proteins--ubiquitin, NEDD8, and SUMO-2--all having almost similar structural features. Two intermediates evolve in the unfolding pathway of each of the three proteins. The first intermediate, which has already been identified in case of ubiquitin by earlier simulation results, is similar for ubiquitin and NEDD8, but different in SUMO-2. We have found a new intermediate with beta3-beta4 hairpin and some residual alpha-helical character; and this intermediate is common for all the three proteins. Thus, proteins of the ubiquitin family pass through a well-defined conformation in their force-induced unfolding pathway. Reason behind the higher mechanical stability of the proteins with parallel strand structures like Titin has also been identified.