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. 2011 Apr;7(4):e1002034.
doi: 10.1371/journal.pcbi.1002034. Epub 2011 Apr 21.

Accessing a Hidden Conformation of the Maltose Binding Protein Using Accelerated Molecular Dynamics

Free PMC article

Accessing a Hidden Conformation of the Maltose Binding Protein Using Accelerated Molecular Dynamics

Denis Bucher et al. PLoS Comput Biol. .
Free PMC article


Periplasmic binding proteins (PBPs) are a large family of molecular transporters that play a key role in nutrient uptake and chemotaxis in Gram-negative bacteria. All PBPs have characteristic two-domain architecture with a central interdomain ligand-binding cleft. Upon binding to their respective ligands, PBPs undergo a large conformational change that effectively closes the binding cleft. This conformational change is traditionally viewed as a ligand induced-fit process; however, the intrinsic dynamics of the protein may also be crucial for ligand recognition. Recent NMR paramagnetic relaxation enhancement (PRE) experiments have shown that the maltose binding protein (MBP) - a prototypical member of the PBP superfamily - exists in a rapidly exchanging (ns to µs regime) mixture comprising an open state (approx 95%), and a minor partially closed state (approx 5%). Here we describe accelerated MD simulations that provide a detailed picture of the transition between the open and partially closed states, and confirm the existence of a dynamical equilibrium between these two states in apo MBP. We find that a flexible part of the protein called the balancing interface motif (residues 175-184) is displaced during the transformation. Continuum electrostatic calculations indicate that the repacking of non-polar residues near the hinge region plays an important role in driving the conformational change. Oscillations between open and partially closed states create variations in the shape and size of the binding site. The study provides a detailed description of the conformational space available to ligand-free MBP, and has implications for understanding ligand recognition and allostery in related proteins.

Conflict of interest statement

The authors have declared that no competing interests exist.


Figure 1
Figure 1. Maltose Binding Protein.
(a) Cartoon representations of the open and closed X-ray structures of MBP (pdb code 1omp and 3mbp [54]). The NTDs of apo and holo MBP are superimposed (grey), and the displacement of the CTD in the open (blue) and closed (red) conformations is shown. The ligand maltotriose is shown in yellow (b) The NMR experiments of Tang et al indicate that the ligand-free protein is in a preexisting dynamical equilibrium between an open and a partially closed conformation.
Figure 2
Figure 2. Accelerated MD trajectories.
(a) Interdomain angles shown here for one set of AMBER simulations (sim1, sim2, sim5). The horizontal lines correspond to the interdomain angle in X-ray structures for the open (apo), and closed (holo) forms. (b) Principal Component Analysis (PCA): The first two PCs were calculated using available X-ray structures in the open and closed states (black, and red points, respectively). The trajectories (in blue) are projected on the space defined by the first 2 principal components (PCs).
Figure 3
Figure 3. Open and semi-closed conformations.
(a) a view from the top of the protein shows the different size and shape of the ligand binding site in the two conformations. A red color indicates that the atoms are close to the binding site, and a blue color that they are >20 Å away. The forward and reverse potential of mean force (PMF) for the displacement of the balancing interface is shown. Residues Ile178 and Leu311 (green) are located in the hinge region, and are buried inside the protein in the semi-closed state. (b) Per residue decomposition of the (MM/GBSA) free energy showing the contribution of each residue to the stability of the open versus the semi-closed state. (c) Color representation of the energy contribution to the open state (blue), versus the semi-closed state (red).
Figure 4
Figure 4. Interdomain hydrogen bonds.
Two hydrogen bonds, absent in the open state (top), are formed in the semi-closed state (bottom): Trp340 (CTD) is found to interact with Asp65 (NTD), and the backbone carbonyl of Glu111 interacts with Tyr155. Both Trp340, and Tyr155 residues are sugar-stacking residues that are also involved in ligand recognition.
Figure 5
Figure 5. Computed and experimental paramagnetic relaxation enhancement rates.
In the upper panels, the black curves are the experimental results, and the red curves are the theoretical results. When only MD trajectories in the open state are considered (left panels), the agreement with experimental PRE is not optimal. However, the agreement is significantly improved by including simulations started in the semi-closed conformation (right panels). The PRE data for the N-terminal domain are represented using open circles, and the PRE data for the C-terminal domain and linker regions are represented using closed circles.

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