title: Conformational changes in protein loops and helices induced by post-translational phosphorylation.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.
authors.forename: Eli S
authors.initials: ES
authors.lastname: Groban
authors.forename: Arjun
authors.initials: A
authors.lastname: Narayanan
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
mesh_terms: D000465:Algorithms; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D019295:Computational Biology; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry; D030562:Databases, Protein; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D008968:Molecular Conformation; D010766:Phosphorylation; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid; D051357:Cyclin-Dependent Kinase 2