A structure-based model fails to probe the mechanical unfolding pathways of the titin I27 domain

Abstract

We discuss the use of a structure based Cα-Go model and Langevin dynamics to study in detail the mechanical properties and unfolding pathway of the titin I27 domain. We show that a simple Go-model does detect correctly the origin of the mechanical stability of this domain. The unfolding free energy landscape parameters x(u) and ΔG(‡), extracted from dependencies of unfolding forces on pulling speeds, are found to agree reasonably well with experiments. We predict that above v = 10(4) nm/s the additional force-induced intermediate state is populated at an end-to-end extension of about 75 Å. The force-induced switch in the unfolding pathway occurs at the critical pulling speed v(crit) ≈ 10(6)-10(7) nm/s. We argue that this critical pulling speed is an upper limit of the interval where Bell's theory works. However, our results suggest that the Go-model fails to reproduce the experimentally observed mechanical unfolding pathway properly, yielding an incomplete picture of the free energy landscape. Surprisingly, the experimentally observed intermediate state with the A strand detached is not populated in Go-model simulations over a wide range of pulling speeds. The discrepancy between simulation and experiment is clearly seen from the early stage of the unfolding process which shows the limitation of the Go model in reproducing unfolding pathways and deciphering the complete picture of the free energy landscape.