title: Inhibition of protein aggregation: supramolecular assemblies of arginine hold the key.
abstract: BACKGROUND
  Aggregation of unfolded proteins occurs mainly through the exposed hydrophobic surfaces. Any mechanism of inhibition of this aggregation should explain the prevention of these hydrophobic interactions. Though arginine is prevalently used as an aggregation suppressor, its mechanism of action is not clearly understood. We propose a mechanism based on the hydrophobic interactions of arginine.
  
  
  METHODS
  We have analyzed arginine solution for its hydrotropic effect by pyrene solubility and the presence of hydrophobic environment by 1-anilino-8-naphthalene sulfonic acid fluorescence. Mass spectroscopic analyses show that arginine forms molecular clusters in the gas phase and the cluster composition is dependent on the solution conditions. Light scattering studies indicate that arginine exists as clusters in solution. In the presence of arginine, the reverse phase chromatographic elution profile of Alzheimer's amyloid beta 1-42 (Abeta(1-42)) peptide is modified. Changes in the hydrodynamic volume of Abeta(1-42) in the presence of arginine measured by size exclusion chromatography show that arginine binds to Abeta(1-42). Arginine increases the solubility of Abeta(1-42) peptide in aqueous medium. It decreases the aggregation of Abeta(1-42) as observed by atomic force microscopy.
  
  
  CONCLUSIONS
  Based on our experimental results we propose that molecular clusters of arginine in aqueous solutions display a hydrophobic surface by the alignment of its three methylene groups. The hydrophobic surfaces present on the proteins interact with the hydrophobic surface presented by the arginine clusters. The masking of hydrophobic surface inhibits protein-protein aggregation. This mechanism is also responsible for the hydrotropic effect of arginine on various compounds. It is also explained why other amino acids fail to inhibit the protein aggregation.
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
authors.forename: Utpal
authors.initials: U
authors.lastname: Das
authors.forename: Gururao
authors.initials: G
authors.lastname: Hariprasad
authors.forename: Abdul S
authors.initials: AS
authors.lastname: Ethayathulla
authors.forename: Pallavi
authors.initials: P
authors.lastname: Manral
authors.forename: Taposh K
authors.initials: TK
authors.lastname: Das
authors.forename: Santosh
authors.initials: S
authors.lastname: Pasha
authors.forename: Anita
authors.initials: A
authors.lastname: Mann
authors.forename: Munia
authors.initials: M
authors.lastname: Ganguli
authors.forename: Amit K
authors.initials: AK
authors.lastname: Verma
authors.forename: Rajiv
authors.initials: R
authors.lastname: Bhat
authors.forename: Sanjeev Kumar
authors.initials: SK
authors.lastname: Chandrayan
authors.forename: Shubbir
authors.initials: S
authors.lastname: Ahmed
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.forename: Punit
authors.initials: P
authors.lastname: Kaur
authors.forename: Tej P
authors.initials: TP
authors.lastname: Singh
authors.forename: Alagiri
authors.initials: A
authors.lastname: Srinivasan
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000737:chemistry* / Q000378:metabolism; D002850:Chromatography, Gel; D051379:Mice; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D001120:Arginine