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N-body Information Theory (NbIT) Analysis of Rigid-Body Dynamics in Intracellular Loop 2 of the 5-HT2A Receptor

Rigid-body motions of protein secondary structure are often implicated in mecha-nisms of protein function. In GPCRs, evidence suggests that intracellular loop 2 (IL2) contains a segment characterized as a helix when the activated receptor trig-gers downstream signaling. However, neither experimental nor computational methods are readily available to assess quantitatively the degree of collective mo-tions in such secondary structure motifs of proteins. Here we describe a new el-ement of our N-body Information Theory (NbIT) framework to address this problem. To this end we introduce total intercorrelation, a measure in infor-mation theory that can be used to describe n-body correlated dynamics between multivariate distributions, such as 3-dimensional atomic fluctuations in simula-tions of proteins. We also define two additional measures, the rigid-body fraction and correlation order, which can be determined from the decomposition of the configurational entropy. Using these measures, we analyze the dynamics of IL2 in microsecond Molecular Dynamics simulations of the 5-HT2A receptor to demonstrate the powerful features of the new analysis techniques in studying the collective motion dynamics of secondary structure motifs. The analysis reveals an intriguing difference in the extent of correlated motions in the helical segment of IL2 in the presence and absence of bound 5-HT, the endogenous agonist that ac-tivates the receptor and triggers downstream signaling, suggesting that IL2 rigid-body motions can display distinct behaviors that may discriminate functional mechanism of GPCRs.