title: Energetics and structural characterization of the large-scale functional motion of adenylate kinase.
abstract: Adenylate Kinase (AK) is a signal transducing protein that regulates cellular energy homeostasis balancing between different conformations. An alteration of its activity can lead to severe pathologies such as heart failure, cancer and neurodegenerative diseases. A comprehensive elucidation of the large-scale conformational motions that rule the functional mechanism of this enzyme is of great value to guide rationally the development of new medications. Here using a metadynamics-based computational protocol we elucidate the thermodynamics and structural properties underlying the AK functional transitions. The free energy estimation of the conformational motions of the enzyme allows characterizing the sequence of events that regulate its action. We reveal the atomistic details of the most relevant enzyme states, identifying residues such as Arg119 and Lys13, which play a key role during the conformational transitions and represent druggable spots to design enzyme inhibitors. Our study offers tools that open new areas of investigation on large-scale motion in proteins.
authors: 1] Department of Chemistry and Applied Biosciences, ETH Zurich, and Faculty of Informatics, Institute of Computational Science, Università della Svizzera Italiana, via G. Buffi 13, CH-6900 Lugano, Switzerland [2] Kimika Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU) and Donostia International Physics Center (DIPC), PK 1072, 20080 Donostia, Euskadi, Spain.
authors: Elena
authors: E
authors: Formoso
authors: 1] Università della Svizzera Italiana (USI), Faculty of Informatics, Institute of Computational Science, via G. Buffi 13, CH-6900 Lugano, Switzerland [2] Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, I-80131 Naples, Italy.
authors: Vittorio
authors: V
authors: Limongelli
authors: Department of Chemistry and Applied Biosciences, ETH Zurich, and Faculty of Informatics, Institute of Computational Science, Università della Svizzera Italiana, via G. Buffi 13, CH-6900 Lugano, Switzerland.
authors: Michele
authors: M
authors: Parrinello
mesh_terms: D000263:Adenylate Kinase / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000263:Adenylate Kinase