title: ClustENM: ENM-Based Sampling of Essential Conformational Space at Full Atomic Resolution.
abstract: Accurate sampling of conformational space and, in particular, the transitions between functional substates has been a challenge in molecular dynamic (MD) simulations of large biomolecular systems. We developed an Elastic Network Model (ENM)-based computational method, ClustENM, for sampling large conformational changes of biomolecules with various sizes and oligomerization states. ClustENM is an iterative method that combines ENM with energy minimization and clustering steps. It is an unbiased technique, which requires only an initial structure as input, and no information about the target conformation. To test the performance of ClustENM, we applied it to six biomolecular systems: adenylate kinase (AK), calmodulin, p38 MAP kinase, HIV-1 reverse transcriptase (RT), triosephosphate isomerase (TIM), and the 70S ribosomal complex. The generated ensembles of conformers determined at atomic resolution show good agreement with experimental data (979 structures resolved by X-ray and/or NMR) and encompass the subspaces covered in independent MD simulations for TIM, p38, and RT. ClustENM emerges as a computationally efficient tool for characterizing the conformational space of large systems at atomic detail, in addition to generating a representative ensemble of conformers that can be advantageously used in simulating substrate/ligand-binding events.
authors: Department of Chemical Engineering and Polymer Research Center, Bogazici University , Bebek 34342, Istanbul, Turkey.
authors: Zeynep
authors: Z
authors: Kurkcuoglu
authors: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania 15213, United States.
authors: Ivet
authors: I
authors: Bahar
authors: Department of Chemical Engineering and Polymer Research Center, Bogazici University , Bebek 34342, Istanbul, Turkey.
authors: Pemra
authors: P
authors: Doruker
mesh_terms: D000263:Adenylate Kinase / Q000737:chemistry / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D016000:Cluster Analysis; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012335:RNA, Ribosomal / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D014305:Triose-Phosphate Isomerase / Q000737:chemistry / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D002147:Calmodulin; D011506:Proteins; D012335:RNA, Ribosomal; D048051:p38 Mitogen-Activated Protein Kinases; D000263:Adenylate Kinase; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D014305:Triose-Phosphate Isomerase