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A structure-based model fails to probe the mechanical unfolding pathways of the titin I27 domain
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Image of FIG. 1.
FIG. 1.

Native state conformation of the I27 domain of titin (PDB ID: 1TIT). There are 8 -strands: A (4–7), A (11–15), B (18–25), C (32–36), D (47–52), E (55–61), F(69–75), and G (78–88). (a) PDB structure in cartoon representation. (b) Schematic view of the same structure. Red and black -strands belong to different -sheets. N- and C-terminal residues are marked N and C, respectively.

Image of FIG. 2.
FIG. 2.

The phase diagram obtained by the extended histogram method. The results were averaged over 30 trajectories. The vertical dashed line marks K at which most of our calculations have been performed.

Image of FIG. 3.
FIG. 3.

Averaged force-extension profiles of the I27 titin domain. The results obtained by Go-model simulations performed at different pulling speeds are shown on the right. The inset shows an enlargement of the starting region. Results have been averaged over 50 trajectories. Values of pulling rates are given in Table I .

Image of FIG. 4.
FIG. 4.

Individual force-extension profiles of the I27 titin domain. Four individual trajectories at 2.5 × 10 nm/s obtained by Go-model simulations are presented. There is no second peak in two trajectories.

Image of FIG. 5.
FIG. 5.

(a)–(f) End-to-end distance dependence of averaged fractions of native contacts. Native contacts are formed by 8 -strands marked in Fig. 1 at different loading rates. Clearly, the unfolding at high forces starts from the C-terminus detaching G-strand first. In contrast, at low forces the A and A strands are unfolded first, but it should be noted that the extension at which complete detachment of the A strand takes place is rather large, 75 Å.

Image of FIG. 6.
FIG. 6.

(a)–(f) End-to-end distance dependence of averaged fractions of native contacts. Same as Fig. 5 but for the end-to-end distance up to 15 Å. Within 15 Å the detachment of the A strand out of the protein core is not observed for any speed studied.

Image of FIG. 7.
FIG. 7.

Typical unfolding pathway of titin from Go-model simulation. Green and blue squares mark AB and AG regions, respectively. The N-terminal residue is shown in magenta. (a) NS conformation. (b) Conformation at 4 Å extension, contacts between AG are missing, both AG and AB remained formed. (c) Conformation at 9 Å extension (after the main peak), contacts between G with A and A are broken, those between the A and B strands are preserved. It should be emphasized that 100% trajectories at the beginning of unfolding (within 10 Å) proceed via the same pathway presented here regardless of the applied pulling rate.

Image of FIG. 8.
FIG. 8.

Typical unfolding pathways of titin. (a)–(d) High pulling speed and (e)–(h) low pulling speed regions. The N-terminal residue is shown in magenta.

Image of FIG. 9.
FIG. 9.

Force dependence on pulling speeds at = 285 K. Force at a given value of pulling speed is computed as an average of maximum forces over 50 trajectories. Grey boundaries of the polygon illustrate the interval of pulling rates used in the AFM experiment. Black circles correspond to data for . Solid and dashed black curves represent linear and nonlinear fits for . Similarly, red color is used for . Straight lines are fits to the Bell-Evans-Ritchie equation (Eq. (7) ), = 109.6 + 9.59ln () and = −90.332 + 12.108ln () for and , respectively. Using a linear fit we found = 3.76 Å and = 2.95 Å for and , respectively. From a nonlinear fit and Eq. (8) , we got = 6.68 Å and Δ = 32.48 for and = 3.88 Å and Δ = 9.22 for . Extrapolation to the experimental pulling speed, = 200 nm/s, gives a negative value of regardless of the fit used. Extrapolated values of to 200 nm/s are 160 and 152 pN using linear and nonlinear fits, respectively.


Generic image for table
Table I.

List of pulling speeds used in simulations. The upper limit for pulling speed used in the AFM experiment is 10 nm/s (taken from Ref. ).


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752b84549af89a08dbdd7fdb8b9568b5 journal.articlezxybnytfddd
Scitation: A structure-based model fails to probe the mechanical unfolding pathways of the titin I27 domain