Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II

55-POS Board 8 Generation of Atomistic Conformers Using Elastic Network Model for Proteins Undergoing Large Conformational Changes and Ribosome

Zeynep Kurkcuoglu , Pemra Doruker. Bogazici University, Istanbul, Turkey.

Efficient computational algorithms are necessary to sample protein conformations for drug design studies, especially in the absence of ligand-bound structures. For this purpose, we developed an unbiased iterative conformational search algorithm based only the apo structure, which combines global modes from elastic network model, clustering and energy minimization with implicit solvation model. At the end of procedure, conformers having a radius of gyration larger than the apo state can be discarded in order to obtain a manageable set for docking applications. The algorithm is applied to five hinge-bending proteins (with conformational changes up to 15 Å RMSD), two proteins showing functional loop motions and the supramolecule ribosome. To assess the performance of generated conformers, known ligands were docked to both relatively closed and intermediate states for adenylate kinase (AK), LAO- binding protein and dipeptide-binding protein. Close-to-holo poses were obtained in all cases. Clustering with the available experimental x-ray and NMR structures (33 for AK, 160 for calmodulin, 24 for biotin carboxylase and 2 structures for the rest of the proteins) indicated that intermediate and/or closed states were sampled during conformation generation. Functional loop motions were also captured by applying the technique to two proteins; triosephosphate isomerase and murA. In order to illustrate the applicability of the algorithm to supramolecules, 70S ribosome conformers were generated embodying its experimentally reported functional motions. Using this computationally efficient method, it is possible to generate conformers for proteins of a wide spectrum, in terms of system size and magnitude of conformational change, which can further be utilized in docking studies.

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