Paper Citing NAMD - Abstract
Masetti, Matteo; Falchi, Federico; Recanatini, Maurizio
Protein Dynamics of the HIF-2 alpha PAS-B Domain upon Heterodimerization and Ligand Binding
PLOS ONE, 9 Art. No. e94986, APR 15 2014
Hypoxia-Inducible Factor (HIF) transcription factors are heterodimeric proteins involved in the regulation of oxygen homeostatis. Their upregulation has been related to several tumors with a remarkably poor clinical outcome. The recent discovery of a druggable cavity in the HIF-2 alpha PAS-B domain has opened an unprecedented opportunity for targeting the HIF-2 alpha transcription factor in view of pharmaceutical strategies. Coincidentally, a novel compound able to selectively disrupt the HIF heterodimerization with a submicromolar activity has been reported. In this work, we investigated the molecular mechanisms responsible for the inhibition by comparing the dynamical features of the HIF-2 alpha PAS-B monomer and the HIF-2 alpha PAS-B/HIF-1 beta PAS-B complex, in the ligand-bound and -unbound states. Plain and biased Molecular Dynamics were used to characterize the differential conformational changes both structurally and energetically.
