Molecular Dynamics Simulations of the Adenosine A2a
Receptor: Structural Stability, Sampling, and Convergence
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Abstract
Molecular
dynamics (MD) simulations of membrane-embedded G-protein
coupled receptors (GPCRs) have rapidly gained popularity among the
molecular simulation community in recent years, a trend which has
an obvious link to the tremendous pharmaceutical importance of this
group of receptors and the increasing availability of crystal structures.
In view of the widespread use of this technique, it is of fundamental
importance to ensure the reliability and robustness of the methodologies
so they yield valid results and enable sufficiently accurate predictions
to be made. In this work, 200 ns simulations of the A2a adenosine
receptor (A2a AR) have been produced and evaluated in the light of
these requirements. The conformational dynamics of the target protein,
as obtained from replicate simulations in both the presence and absence
of an inverse agonist ligand (ZM241385), have been investigated and
compared using principal component analysis (PCA). Results show that,
on this time scale, convergence of the replicates is not readily evident
and dependent on the types of the protein motions considered. Thus
rates of inter- as opposed to intrahelical relaxation and sampling
can be different. When studied individually, we find that helices
III and IV have noticeably greater stability than helices I, II, V,
VI, and VII in the apo form. The addition of the inverse agonist ligand
greatly improves the stability of all helices