Close correspondence between the motions from principal component analysis of multiple HIV-1 protease structures and elastic network modes - PubMed (original) (raw)

Close correspondence between the motions from principal component analysis of multiple HIV-1 protease structures and elastic network modes

Lei Yang et al. Structure. 2008 Feb.

Abstract

The large number of available HIV-1 protease structures provides a remarkable sampling of conformations of the different conformational states, which can be viewed as direct structural information about the dynamics of the HIV-1 protease. After structure matching, we apply principal component analysis (PCA) to obtain the important apparent motions for both bound and unbound structures. There are significant similarities between the first few key motions and the first few low-frequency normal modes calculated from a static representative structure with an elastic network model (ENM), strongly suggesting that the variations among the observed structures and the corresponding conformational changes are facilitated by the low-frequency, global motions intrinsic to the structure. Similarities are also found when the approach is applied to an NMR ensemble, as well as to molecular dynamics (MD) trajectories. Thus, a sufficiently large number of experimental structures can directly provide important information about protein dynamics, but ENM can also provide similar sampling of conformations.

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Figures

Figure 1

Figure 1

Cartoon representation (A) and alpha carbon trace (B) of the HIV-1 protease structure. Blue - the flap domain; green - the core domain; cyan - the terminal domain; yellow - other residues. The red spheres represent the conserved Asp25-Thr26-Gly27 active site triad. The figure was created using PyMOL (DeLano Scientific).

Figure 2

Figure 2

RMSD with respect to the reference structure for: (A) X-ray-I dataset, with the RMSD values sorted in ascending order. X-ray-II dataset is the same as X-ray-I, excluding the eight structures that have significantly larger RMSD values than the rest. (B) NMR dataset, sorted by the RMSD values in ascending order. (C) MD dataset, shown in the order of the time steps along the 10 ns simulation. (D) MD dataset, sorted by the RMSD values in ascending order.

Figure 3

Figure 3

The fraction of variance (‘o’) and the cumulative fraction of variance (‘x’) represented by the first 6 PCs for: (A) X-ray-I dataset. (B) X-ray-II dataset. (C) NMR dataset. (D) MD dataset.

Figure 4

Figure 4

Distribution of individual structures along pairs of the first three principal component directions. Shown are the planes of PC 1 and PC 2 and of PC 1 and PC 3 for X-ray-I, X-ray-II, NMR and MD datasets respectively. (For the MD dataset, the 10,000 data points are represented by 100 data points by coarse-graining.)

Figure 5

Figure 5

Residue positional fluctuations of the first 3 PCs in each dataset. Note that the PC 1 and PC 2 in the X-ray-I dataset have symmetrical fluctuations for the two protein chains (the first chain: residues 1–99; the second chain: residues 100–198). But no symmetrical fluctuations are observed for the X-ray-II, NMR and MD datasets.

Figure 6

Figure 6

Visualizations of the motions of the dominant PCs (left column) and the most similar corresponding modes predicted by ENM (right column). In the X-ray-II dataset, the overlap between (A) PC 1 and (B) Mode 2 is 0.52. In the NMR dataset, the overlap between (C) PC 1 and (D) Mode 2 is 0.91. In the MD dataset, the overlap between (E) PC 1 and (F) Mode 1 is 0.74. Blue - the flap domain; green - the core domain; cyan - the terminal domain; yellow - other residues. The motions of PCs and modes are shown as red sticks with the directions indicated. The stick lengths represent the relative amplitudes of fluctuations of the corresponding residue.

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