Structural simulations and novel analysis pipelines on the ligand-binding domain of pathologic glucocorticoid receptors

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIAID	STRUCTBIO-7

Authors

D.E. Hurt
T. Mayama
E. Charmandari
T. Kino
Y. Huyen

Abstract

Generalized glucocorticoid resistance syndrome is a rare, genetic condition characterized by partial insensitivity to glucocorticoids and most affected subjects present with clinical manifestations of mineralocorticoid and androgen excess. The syndrome is caused by mutations to the human glucocorticoid receptor (GR), which impair its abilities to bind glucocorticoids and to activate transcription of genes through communication with coactivators containing an LXXLL sequence motif. Most of the known pathologic mutations are located on the ligand-binding domain of GR, although many of them are not directly associated with the ligand-binding pocket or the LXXLL-binding groove. We used molecular dynamics simulations to understand how these mutations might affect binding events. Although there are few obvious structural changes due to the mutations, careful statistical analysis of binding energies, pocket volumes, binding surface areas, and patterns of intermolecular contacts reveal good correlation of these metrics to experimentally-determined changes in ligand affinity. We share here methods of traditional structural analysis extended to molecular dynamics trajectories, which permit the application of statistical tests and the development of p values to elucidate subtle changes and allosteric effects of distant mutations.