Conformational changes in protein loops and helices induced by post-translational phosphorylation.

PLoS Computational Biology
Eli S GrobanMatthew P Jacobson

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 illustra...Continue Reading

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Methods Mentioned

BETA
nuclear magnetic resonance
circular dichroism
X-ray

Software Mentioned

Chimera
Jaguar
CONGEN
Impact

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