Active and Inactive Confo... - Yale Image Finder

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Figure 7: Active and Inactive Conformations of the CDK2 Activation LoopLeft: Blue represents the crystal structures of the phospho-CDK2/cyclin A complex, and green represents the T160E-predicted active-like conformation. The Arg cluster is shown in stick representation. The carboxylate group of Glu160 and the phosphate group of pThr160 are almost exactly superimposed. Right: Purple represents the crystal structure of unphosphorylated CDK2/cyclin A, and yellow represents the predicted inactive conformation of T160E. These two structures are qualitatively similar in that Thr160 and Glu160 both point out into solvent and the Arg cluster is better solvated. Figures prepared with Chimera [72].

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Abstract

Post-translational phosphorylation is a ubiquitous mechanism for modulating protein activity and protein-protein interactions. In this work, we examine how phosphorylation can modulate the conformation of a protein by changing the energy landscape. We present a molecular mechanics method in which we phosphorylate proteins in silico and then predict how the conformation of the protein will change in response to phosphorylation. We apply this method to a test set comprised of proteins with both phosphorylated and non-phosphorylated crystal structures, and demonstrate that it is possible to predict localized phosphorylation-induced conformational changes, or the absence of conformational changes, with near-atomic accuracy in most cases. Examples of proteins used for testing our methods include kinases and prokaryotic response regulators. Through a detailed case study of cyclin-dependent kinase 2, we also illustrate how the computational methods can be used to provide new understanding of how phosphorylation drives conformational change, why substituting Glu or Asp for a phosphorylated amino acid does not always mimic the effects of phosphorylation, and how a phosphatase can “capture” a phosphorylated amino acid. This work illustrates how computational methods can be used to elucidate principles and mechanisms of post-translational phosphorylation, which can ultimately help to bridge the gap between the number of known sites of phosphorylation and the number of structures of phosphorylated proteins.