24 research outputs found

    Structures with intermediate-scale motions.

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    <p>(A) Triosephosphate Isomerase (TIM) has a mobile loop that covers the active site (orange). The mobile loop has been crystallized in both an open [8tim] (green) and closed [1TPH] (blue) conformations. (B) Dihydrofolate Reductase (DHFR) pos-sesses the Met20-loop that has been crystallized in three different states - open [1RA2] (green), closed [1RX2] (blue) and occluded [1RX7] (purple). There is experimental evidence that the Met20-loop interacts with the adenosine-binding loop, the F–G loop and the G–H loop. (C) α-Lytic protease (αLP) [1SSX] is the control as it is a kinetically-stable protease (catalytic triad in orange) that does not possess any mobile loops. (D) The Estrogen Receptor (ER) has a highly mobile Helix-12 that covers the ligand (red) binding site. ER has been crystallized in a closed [1QKU] (blue) and open [1QKT] (green) conformation. (E) The N-terminal domain of the chaperone HSP90 (HSP90) has a 23 amino acid lid [2IOR] (green) that undergoes a large conformational change to bind ADP [2IOQ] (blue).</p

    RIP-induced conformation changes of TIM.

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    <p>(A) the Cα RMSD response to the perturbation of RIP on Glu128 (red arrow) shown after 2 ps (blue) and at the end of the 10 ps simulation (green). (B) The 10th ps conformation (red) of the TIM structure due to RIP on Glu128 (red spheres), overlaid over the closed state (blue) and open state (green) of the crystal structures. (C) The frequency distribution of Cα RMSD for all residues from the entire set of perturbations of RIP over every residue in TIM.</p

    RIP perturbations of Estrogen Receptor (ER).

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    <p>(A) RIP deformation map. (B) Structural linchpins and perturbation strength histogram. (C) Local flexibility mapped on structure and in histogram. Colors are as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000343#pcbi-1000343-g004" target="_blank">Figure 4</a>.</p

    RIP perturbations of HSP90.

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    <p>(A) RIP deformation map. (B) Structural linchpins and per-turbation strength histogram. (C) Local flexibility mapped on structure and in histogram. Colors are as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000343#pcbi-1000343-g004" target="_blank">Figure 4</a>.</p

    Trajectories of pulling the I27 domain of titin with constant-momentum.

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    <p>(A) Schematic of I27 for target pulling [1TIT]. The key interactions for the unfolding intermediate are the hydrogen bonds (blue) between β-strand-A' and β-strand-B, and between β-strand-A and β-strand-G. In the pulling experiments and simulations, the anchor points for the pulling are the N and C terminii (red). (B) The trajectory for a target velocity of 6.0 Å/ps shows constant velocity motion with a fitted slope of 5.9 Å/ps. (C) The pre-pulse velocities fluctuate around 4.1 Å/ps except for the early part of the trajectory where the velocities is close to zero. (D) The applied forces derived from the change in velocities from the pre-pulse velocities to the target velocity (dark blue). As the forces fluctuate ∼150 pN, to find the general shape of the curve (light blue), a low-pass FFT filter was used to filter out the fluctuations. The fitted curve has a maximum of 280 pN near the beginning of the trajectory before dropping down to ∼20 pN. In the second column are the results for the trajectory with a target velocity of 1.00 Å/ps. (E) The system is effectively trapped as the distance between the anchor points do not change. (F) The pre-pulse velocities are negative −0.7 Å/ps, due to the reflection against the free-energy barrier. (G) The applied forces. The fitted curve has a maximum of 93 pN that is maintained throughout the simulation.</p

    Analysis of the response of I27 to constant-momentum pulling over a range of target velocities.

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    <p>(A) In the distance response curves, the points along each column represents the distance evolution of the trajectory for a given target velocity. If the last point approaches the gray dotted line, the protein is unfolding at the target velocity rate. Otherwise the protein is trapped by an unfolding barrier. (B) In the velocity response curves the averaged pre-pulse velocity is plotted for each trajectory. Negative values means the protein is trapped in an intermediate or is completely extended. When the protein is unfolding without barriers, the values approaches the positive dotted curve. (C) In the fitted force response curves, the forces can be compared to the theoretical maximum force (2MV<sub>target</sub>) indicated by the gray line. When the system is trapped or completely extended, the maximum force is close the the theoretical maximum. When the system is unfolding with no barriers, the maximum force plateaus at the unfolding force of the protein.</p

    RIP perturbations of Dihydrofolate Reductase (DHFR).

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    <p>(A) RIP deformation map. (B) Structural linchpins and perturbation strength histogram. (C) Local flexibility mapped on structure and in histogram. Colors are as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000343#pcbi-1000343-g004" target="_blank">Figure 4</a>.</p

    Comparison of the RIP method to standard molecular dynamics using methyl-capped amino acids.

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    <p>(A) The correlation of the average rotational velocities of the χ angles of the 17 amino acids that possess χ angles. Units are in [rad ps<sup>−1</sup>]. In the graph, the Y-axis standard velocities (extracted from standard molecular-dynamics at 300 K) are plotted against the X-axis RIP velocities (in the RIP protocol the kinetic energy at 300 K are effectively transferred to the χ-angle degrees of freedom). The correlation coefficient is 0.84. Detailed comparison for ILE (which has two χ-angles) of the standard molecular-dynamics simulation to the RIP simulation. (B) The distributions of the average kinetic energy per atom are fairly similar. The differences can be seen in the (C) distribution of the χ1 rotational velocities and (D) distributions of the χ2 rotational velocities.</p

    Conformational change in Helix-12 of the Estrogen Receptor ligand-binding domain.

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    <p>(A) Overlay of the crystal structures showing Helix-12 in the closed conformation (blue) and the open conformation (green), which indicates the pivot point between the two structures. In the RIP simulations, perturbation on Trp-83 (red spheres) induces a large conformational change in Helix-12 (red), from the starting conformation of the closed structure (blue), where the hinge of the perturbed motion corresponds to the pivot point of the crystal structures.</p

    The constant-momentum simulations for the different pulling geometries of e2lip3 and ubiquitin.

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    <p>The pulling geometries are (A,B) N-C pulling in e2lip3, (C,D) N-41 pulling in e2lip3, (E,F) N-C pulling in ubiquitin, and (G,H) 48-C pulling in ubiquitin. The left column shows the schematic whilst the right column shows the distance-response curve as explained in the captions for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013068#pone-0013068-g002" target="_blank">Figure 2(A)</a>. By identifying where the major drop-off in distance response occurs, we can identify the critical target velocity, from which we can derive a critical unfolding force.</p
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