Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes

Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al

Symmetry-Dependent Vibrational Circular Dichroism Enhancement in Co(II) Salicylaldiminato Complexes

Chiral coordination compounds of Co(II) and other open-shell metal complexes display enhanced vibrational circular dichroism (VCD) spectra associated with the existence of low-lying excited states (LLESs). In addition to the enhancement, a series of Co(II) salicylaldiminato complexes exhibits an almost monosignate pattern of VCD bands, a unique feature if compared with the usual alternation of positive and negative signals. Frequency and excited-state calculations reveal that VCD enhancement and sign reversal selectively affect the normal modes of B symmetry of the C 2 -symmetric pseudotetrahedral species thanks to their combination with one or more LLES having the same B symmetry. This proves the strict relation between VCD enhancement and monosignate appearance and demonstrates an unprecedented symmetry dependence of the two phenomena