title: Exploring the molecular mechanism of trimethylamine-N-oxide's ability to counteract the protein denaturing effects of urea.
abstract: Protein denaturation in highly concentrated urea solution is a well-known phenomenon. The counteracting effect of a naturally occurring osmolyte, trimethylamine-N-oxide (TMAO), against urea-conferred protein denaturation is also well-established. However, what is largely unknown is the mechanism by which TMAO counteracts this denaturation. To provide a molecular level understanding of how TMAO protects proteins in highly concentrated urea solution, we report here the structural, energetic, and dynamical properties of N-methylacetamide (NMA) solutions that also contain urea and/or TMAO. The solute NMA is of interest mainly because it contains the peptide linkage in addition to hydrophobic sites and represents the typical solvent-exposed state of proteins. Molecular dynamics computer simulation technique is employed in this study. Analysis of solvation characteristics reveals dehydration of NMA and reduction in hydrogen bond number between NMA oxygen and water upon addition of TMAO. The effect of TMAO on NMA-urea interaction is found to be insignificant. Because TMAO cannot donate its hydrogen to NMA oxygen, the total number of hydrogen bonds formed by NMA oxygen with solution species decreases in the presence of TMAO. In solution, TMAO is found to interact strongly with water and urea. Solvation of TMAO makes the water hydrogen bonding network relatively stronger and reduces relaxation of urea-water hydrogen bonds. Implications of these results for counteracting mechanism of TMAO are discussed.
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Guwahati Assam, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Sarma
authors.forename: Sandip
authors.initials: S
authors.lastname: Paul
mesh_terms: D006860:Hydrogen Bonding; D008744:Methylamines / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011489:Protein Denaturation; D011506:Proteins / Q000737:chemistry*; D014508:Urea / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D008744:Methylamines; D011506:Proteins; D014867:Water; D014508:Urea; C005855:trimethyloxamine