37 research outputs found
Persistent Protein Motions in a Rugged Energy Landscape Revealed by Normal Mode Ensemble Analysis
Testing
the premise of evolutionarily optimized protein dynamics has remained an experimental
challenge. Most measurements fail to
isolate specific structural motions. Our
simulations show that the structural variation of a single protein in time
results in variation in the vibrations leading to the observed broad and
featureless optical absorption. However,
when the thermal population of a protein’s configurations are considered,
vibrations with functional displacements are concentrated in specific frequency
bands. These emergent dynamics are
apparent in anisotropic optical absorbance, indicating an experimental avenue
for measuring these motions and their impact on biological function
Concerted Interconversion between Ionic Lock Substates of the β2 Adrenergic Receptor Revealed by Microsecond Timescale Molecular Dynamics
The recently solved crystallographic structures for the A2A adenosine receptor and the β1 and β2 adrenergic receptors have shown important differences between members of the class-A G-protein-coupled receptors and their archetypal model, rhodopsin, such as the apparent breaking of the ionic lock that stabilizes the inactive structure. Here, we characterize a 1.02 μs all-atom simulation of an apo-β2 adrenergic receptor that is missing the third intracellular loop to better understand the inactive structure. Although we find that the structure is remarkably rigid, there is a rapid influx of water into the core of the protein, as well as a slight expansion of the molecule relative to the crystal structure. In contrast to the x-ray crystal structures, the ionic lock rapidly reforms, although we see an activation-precursor-like event wherein the ionic lock opens for ∼200 ns, accompanied by movements in the transmembrane helices associated with activation. When the lock reforms, we see the structure return to its inactive conformation. We also find that the ionic lock exists in three states: closed (or locked), semi-open with a bridging water molecule, and open. The interconversion of these states involves the concerted motion of the entire protein. We characterize these states and the concerted motion underlying their interconversion. These findings may help elucidate the connection between key local events and the associated global structural changes during activation