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

TL;DR

This study evaluates a structure-based Go-model's ability to simulate the mechanical unfolding of titin I27, finding it captures some stability features but fails to reproduce the experimentally observed unfolding pathway.

Contribution

The paper demonstrates that while a simple Go-model can estimate stability parameters, it inadequately models the unfolding pathway of titin I27, highlighting its limitations.

Findings

Go-model accurately predicts stability parameters

Discrepancy in unfolding pathway simulation

Critical pulling speed estimated around 10^6-10^7 nm/s

Abstract

We discuss the use of a structure based C$\alpha$-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 $\Delta G^{\ddagger}$, 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 $75 \mathring{A}$. The force-induced switch in the unfolding pathway occurs at the critical pulling speed $v_{crit} \approx 10^6-10^7$ 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.