Int J Biochem Mol Biol 2011;2(2):190-198

Original Article
Characterization of ligand type of estrogen receptor by MD simulation and mm-PBSA
free energy analysis

Jing-Yuan Liu, Sean D. Mooney

Center for Computational Biology and Bioinformatics, Department of Medical and Molecular Genetics, Indiana University School of Medicine,
Indianapolis, Indiana

Received April 18, 2011; accepted April 21, 2011; Epub April 23, 2011; Published April 30, 2011

Abstract: Estrogen receptor is a transcription regulator and can bind structurally distinct ligands with full agonistic, SERMs, or full antagonistic
properties. Crystal structures of the ER ligand binding domain (LBD)-complexed with full agonists or SERMs show that these ligands induce
two different orientations of Helix12 in LBD and generate two different conformations, agonist conformation (A conformation) and AF2
antagonist conformation (B conformation). To understand how ER ligands interact with LBD structurally and energetically, we docked 3 full
agonists, 9 SERMs and 2 full antagonists in both the A and B conformation of ERα LBD and performed a 4-step molecular dynamics (MD)
simulation on all 28 complexes followed by mm-PBSA binding free energy calculation. We found that all full agonists prefer the A conformation
while all SERMs prefer the B conformation. Analysis of the mm-PBSA energies revealed that calculated total binding free energies (delta
PBTOT) and the difference of VDW between complex and the sum of receptor and ligand (delta VDW) have the order of full agonists>
SERMs>full antagonists. However, the PB surface term have the order of full antagonists>SERMs>full agonists. We also found that the sum of
the RMSD of mainchain atoms of Helix12 and all atoms of ligands in the A conformation are significantly lower for full agonists than that of the
other ligands. Together, we conclude that the three types of ER ligands interact with the A and B conformations of ERα LBD differently and
same type of ligands interact simlarly. These findings will be useful in understanding the mechanism of ER antagonism and can be used in
ligand type prediction.(IJBMB1104006).

Keywords: Estrogen receptor, antagonism, full agonist, full antagonist, SERM, agonist conformation, AF2 antagonist conformation

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Address all correspondence to:
Sean D. Mooney, PhD
Buck Institute 8001 Redwood Blvd. Novato,
CA 94945, USA.
Tel: 415-209-2038; Fax: 415-209-9920;