From Protein Structure to Function with Bioinformatics.pdf

9 Protein Dynamics: From Structure to Function 241Fig. 9.12 Comparison of the sampling properties of Molecular Dynamics and CONCOORD onhypothetic energy landscapes. A MD-trajectory (left) “walks” on the energy landscape, therebyproviding information about timescales and paths between conformational substates. The (nondeterministic)CONCOORD-ensemble (right) “jumps” on the energy landscape, thereby offeringbetter sampling of the conformational spaceFig. 9.13 Left: Overlay of X-ray structures of adenylate kinase. Right: principal componentanalysis. Two tCONCOORD ensembles are projected onto the first two eigenvectors of a PCAcarried out on an ensemble of X-ray structures. The ensemble represented by red dots has beenstarted from a closed conformation (1AKE) with removed inhibitor. The generated ensemblesamples both, closed and open conformations. The ensemble represented with green dots has alsobeen started from a closed conformation (1AKE) but with inhibitor present. The generatedensemble only samples closed conformations around the ligand bound conformationpredicting ligand-bound structures from unbound conformations, needs to beaddressed. A tCONCOORD simulation starting with an open conformation(4AKE) as input produced structures that approach the closed conformationswith RMSD’s of 2.5, 2.9, and 3.3 Å for 1DVR, 1AK2, and 1AKE, respectively.Thus, the functional domain-opening motion has been predicted in both cases,when using a closed, ligand-bound conformation as input and when using anopen, ligand-free conformation as input.Because of its computational efficiency, CONCOORD can be routinely appliedto extract functionally relevant modes of flexibility for molecular systems that arebeyond the size limitations of other atomistic simulation techniques like moleculardynamics simulations. An application to the chaperonin GroEL-GroES complex