Paper Citing NAMD - Abstract
Huang, Wei; Greene, Geoffrey L.; Ravikumar, Krishnakumar M.; Yang, Sichun
Cross-talk between the ligand- and DNA-binding domains of estrogen receptor
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 81:1900-1909, NOV 2013
Estrogen receptor alpha (ER) is a hormone-responsive transcription factor that contains several discrete functional domains, including a ligand-binding domain (LBD) and a DNA-binding domain (DBD). Despite a wealth of knowledge about the behaviors of individual domains, the molecular mechanisms of cross-talk between LBD and DBD during signal transduction from hormone to DNA-binding of ER remain elusive. Here, we apply a multiscale approach combining coarse-grained (CG) and atomistically detailed simulations to characterize this cross-talk mechanism via an investigation of the ER conformational landscape. First, a CG model of ER is built based on crystal structures of individual LBDs and DBDs, with more emphasis on their interdomain interactions. Second, molecular dynamics simulations are implemented and enhanced sampling is achieved via the push-pull-release strategy in the search for different LBD-DBD orientations. Third, multiple energetically stable ER conformations are identified on the landscape. A key finding is that estradiol-bound LBDs utilize the well-described activation helix H12 to pack and stabilize LBD-DBD interactions. Our results suggest that the estradiol-bound LBDs can serve as a scaffold to position and stabilize the DBD-DNA complex, consistent with experimental observations of enhanced DNA binding with the LBD. Final assessment using atomic-level simulations shows that these CG-predicted models are significantly stable within a 15-ns simulation window and that specific pairs of lysine residues in close proximity at the domain interfaces could serve as candidate sites for chemical cross-linking studies. Together, these simulation results provide a molecular view of the role of ER domain interactions in response to hormone binding. Proteins 2013; 81:1900-1909. (c) 2013 Wiley Periodicals, Inc.
