110
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.
