title: Molecular Dynamics Simulation of Tau Peptides for the Investigation of Conformational Changes Induced by Specific Phosphorylation Patterns.
abstract: The Tau protein plays an important role due to its biomolecular interactions in neurodegenerative diseases. The lack of stable structure and various posttranslational modifications such as phosphorylation at various sites in the Tau protein pose a challenge for many experimental methods that are traditionally used to study protein folding and aggregation. Atomistic molecular dynamics (MD) simulations can help around deciphering relationship between phosphorylation and various intermediate and stable conformations of the Tau protein which occur on longer timescales. This chapter outlines protocols for the preparation, execution, and analysis of all-atom MD simulations of a 21-amino acid-long phosphorylated Tau peptide with the aim of generating biologically relevant structural and dynamic information. The simulations are done in explicit solvent and starting from nearly extended configurations of the peptide. The scaled MD method implemented in AMBER14 was chosen to achieve enhanced conformational sampling in addition to a conventional MD approach, thereby allowing the characterization of folding for such an intrinsically disordered peptide at 293 K. Emphasis is placed on the analysis of the simulation trajectories to establish correlations with NMR data (i.e., chemical shifts and NOEs). Finally, in-depth discussions are provided for commonly encountered problems.
authors.affiliation: School of Biomedical Sciences, CHIRI Biosciences and Curtin Institute for Computation, Curtin University, G.P.O. Box U1987, Perth, WA, 6845, Australia. Neha.Gandhi@curtin.edu.au.
authors.forename: Neha S
authors.initials: NS
authors.lastname: Gandhi
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Predrag
authors.initials: P
authors.lastname: Kukic
authors.affiliation: Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, Université de Toulouse, CNRS, INRA, INSA Toulouse, 135Avenue de Rangueil, 31077, Toulouse, France.|Université de Lille, CNRS, UMR 8576, UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.affiliation: School of Biomedical Sciences, CHIRI Biosciences and Curtin Institute for Computation, Curtin University, G.P.O. Box U1987, Perth, WA, 6845, Australia. R.Mancera@curtin.edu.au.
authors.forename: Ricardo L
authors.initials: RL
authors.lastname: Mancera
mesh_terms: D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D017510:Protein Folding; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D010455:Peptides; D016875:tau Proteins
keywords: AMBER; Antibody; Free energy surface; Phosphorylation; Protein folding; Scaled molecular dynamics simulation; Tau protein