title: Microscopic insights into the protein-stabilizing effect of trimethylamine N-oxide (TMAO).
abstract: Although it is widely known that trimethylamine N-oxide (TMAO), an osmolyte used by nature, stabilizes the folded state of proteins, the underlying mechanism of action is not entirely understood. To gain further insight into this important biological phenomenon, we use the C≡N stretching vibration of an unnatural amino acid, p-cyano-phenylalanine, to directly probe how TMAO affects the hydration and conformational dynamics of a model peptide and a small protein. By assessing how the lineshape and spectral diffusion properties of this vibration change with cosolvent conditions, we are able to show that TMAO achieves its protein-stabilizing ability through the combination of (at least) two mechanisms: (i) It decreases the hydrogen bonding ability of water and hence the stability of the unfolded state, and (ii) it acts as a molecular crowder, as suggested by a recent computational study, that can increase the stability of the folded state via the excluded volume effect.
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104; andUltrafast Optical Processes Laboratory, Philadelphia, PA 19104.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104; andUltrafast Optical Processes Laboratory, Philadelphia, PA 19104.
authors.forename: Ileana M
authors.initials: IM
authors.lastname: Pazos
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104; andUltrafast Optical Processes Laboratory, Philadelphia, PA 19104 gai@sas.upenn.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Gai
mesh_terms: D006860:Hydrogen Bonding / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008744:Methylamines / Q000494:pharmacology*; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation / Q000187:drug effects*; D017510:Protein Folding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D058767:Protein Unfolding / Q000187:drug effects; D011506:Proteins / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D014508:Urea / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D008744:Methylamines; D008840:Microfilament Proteins; D010455:Peptides; D011506:Proteins; C026615:villin; D014867:Water; D014508:Urea; C005855:trimethyloxamine
keywords: 2D IR; crowding; infrared; linear response function