title: Physical basis for the ofloxacin-induced acceleration of lysozyme aggregation and polymorphism in amyloid fibrils.
abstract: Aggregation of globular proteins is an intractable problem which generally originates from partially folded structures. The partially folded structures first collapse non-specifically and then reorganize into amyloid-like fibrils via one or more oligomeric intermediates. The fibrils and their on/off pathway intermediates may be toxic to cells and form toxic deposits in different human organs. To understand the basis of origins of the aggregation diseases, it is vital to study in details the conformational properties of the amyloidogenic partially folded structures of the protein. In this work, we examined the effects of ofloxacin, a synthetic fluoroquinolone compound on the fibrillar aggregation of hen egg-white lysozyme. Using two aggregation conditions (4M GuHCl at pH 7.0 and 37 °C; and pH 1.7 at 65 °C) and a number of biophysical techniques, we illustrate that ofloxacin accelerates fibril formation of lysozyme by binding to partially folded structures and modulating their secondary, tertiary structures and surface hydrophobicity. We also demonstrate that Ofloxacin-induced fibrils show polymorphism of morphology, tinctorial properties and hydrophobic surface exposure. This study will assist in understanding the determinant of fibril formation and it also indicates that caution should be exercised in the use of ofloxacin in patients susceptible to various aggregation diseases.
authors.affiliation: Biophysical Chemistry & Structural Biology Laboratory, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Vidyanagari Campus, Mumbai 400098, India.
authors.forename: Shivani A
authors.initials: SA
authors.lastname: Muthu
authors.affiliation: Biophysical Chemistry & Structural Biology Laboratory, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Vidyanagari Campus, Mumbai 400098, India.
authors.forename: Nivin
authors.initials: N
authors.lastname: Mothi
authors.affiliation: Biophysical Chemistry & Structural Biology Laboratory, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Vidyanagari Campus, Mumbai 400098, India.
authors.forename: Sonali M
authors.initials: SM
authors.lastname: Shiriskar
authors.affiliation: Molecular Simulations Group, Department of Pharmaceutical Chemistry, Goa College of Pharmacy, Panaji, Goa 403001 India.
authors.forename: Raghuvir R S
authors.initials: RR
authors.lastname: Pissurlenkar
authors.affiliation: Biophysical Chemistry & Structural Biology Laboratory, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Vidyanagari Campus, Mumbai 400098, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Biophysical Chemistry & Structural Biology Laboratory, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Vidyanagari Campus, Mumbai 400098, India. Electronic address: ahmad.basir1@gmail.com.
authors.forename: Basir
authors.initials: B
authors.lastname: Ahmad
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D003460:Crystallization; D004789:Enzyme Activation; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D009113:Muramidase / Q000737:chemistry* / Q000648:ultrastructure*; D015242:Ofloxacin / Q000737:chemistry*; D066329:Protein Aggregates; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D015242:Ofloxacin; C421864:hen egg lysozyme; D009113:Muramidase
keywords: Amyloid fibrils; Biophysical techniques; Fibril polymorphism; Lysozyme; Systemic amyloidoses