Dynamic communication between androgen and coactivator: mutually induced conformational perturbations in androgen...

The transcriptional activity of androgen receptor (AR) is regulated by the sequential binding of various ligands (e.g., dihydrotestosterone, DHT) and coactivators (e.g., SRC/p160) to the AR ligand binding domain (LBD) (Askew et al., J Biol Chem 2007; 282:25801-25816, Lee and Chang, Cell Mol Life Sci 2003;60:1613-1622). However, the synergism between the recruitments of coactivator (SRC 2-3) and ligand (such as DHT) to AR at atomic level remains unclear. Thus, in this work, extensive explicit-solvent molecular dynamics (MD) simulations on four independent trajectories, that is, AR-apo (unbound), DHT·AR, AR·SRC, and DHT·AR·SRC, are performed to investigate the potential communications between the two events in the AR transcriptional process. The MD simulations, analysis of the dynamical cross-correlation maps, comparisons of the binding energy, and thermodynamic analysis reveal a definite structural and functional link between Activation Function-2 (AF-2) surface and the ligand binding site influenced by the binding of ligand and coactivator to the LBD: (I) The DHT binding can increase the LBD volume to 753.0 A³ from its compact ligand-free state (372.1 A³), resulting in a group of helices (1, 2, 8, and loop 20) to move outward and exert added traction on the ligand binding pathway, which subsequently leads to rearrange the AF-2 region to well recruit the SRC; (II) Similarly, the SRC recruitment is also found to facilitate the ligand binding through transmitting a concomitant push-pull effort from the AF-2 surface to the DHT binding site, leading to the opening of entrance to the LBD formed by Val684, Met745, and Arg752, increase of the volume of binding pocket (896.4 A³) and stabilization of the dynamic structure of the LBD. These results, in a dynamic form, initially show a bidirectional structural and functional relay between the bound DHT and SRC that establishes AR functional potency.