Model Dependency of TMAO’s Counteracting Effect Against Action of Urea: Kast Model versus Osmotic Model of TMAO

Abstract

Classical molecular dynamics simulation of GB1 peptide (a 16-residue β-hairpin) in different osmotic environments is studied. Urea is used for denaturation of the peptide, and trimethylamine-N-oxide (TMAO) is used to offset the effect of urea. Protein-urea electrostatic interactions are found to play a major role in protein-denaturation. To emphasize on protein protecting action of TMAO against urea, two different models of TMAO are used, viz., the Kast model and the Osmotic model. We observe that the Osmotic model of TMAO gives the best protection to counteract urea's action when used in ratio 1:2 of urea:TMAO (i.e., reverse ratio). This is because the presence of TMAO makes urea-protein electrostatic interactions more unfavorable. Preferential solvation of TMAO molecules by urea (and water) molecules is also observed, which causes depletion in the number of urea molecules in the vicinity of the protein. The calculations of intraprotein hydrogen bonds between different residues of protein further reveal the breaking of backbone hydrogen bonds of residues 2 and 15 in the presence of urea, and the same is preserved in the presence of TMAO. Free energy landscapes show that the narrowest distribution is obtained for the osmotic TMAO model when used in reverse ratio.

Crowders and Cosolvents—Major Contributors to the Cellular Milieu and Efficient Means to Counteract Environmental Stresses

“…Consequently, an enhanced hydration shell would prevent the attack by urea . This is consistent with recent MD simulations suggesting that TMAO counteracts the destabilizing effect of urea by removing the denaturant from the protein surface …”

“…[57] This is consistent with recent MD simulations suggesting that TMAO counteracts the destabilizing effect of urea by removing the denaturant from the protein surface. [92,93] Interestingly,t here is also ac lose connection between the osmoticp ressure of the cosolvents olution and its impact on biomolecules. Theo smotic pressure of the solution, p,a ssuming ideal solution conditions, is given by the van't Hoff law, i.e., p ideal ¼ cRT,w here c = n osm /V is the molar concentration of the solute (osmolyte) per Lo fs olution (osmolarity, osmolL À1 ).…”

Trimethylamine-N-oxide: its hydration structure, surface activity, and biological function, viewed by vibrational spectroscopy and molecular dynamics simulations

“…Indeed, classical MD simulations suggest that the situation of TMAO and urea may be drastically different if an interface is present, 94,95 while it needs to be stressed that for such studies the choice of the force-field models is extremely critical. 94,96 Therefore, only advances in both experimental methods and computational studies will be able to shed light on the underlying mechanisms for such complex multi-component systems.…”

Effect of TMAO and Urea on Dimers and Tetramers of Amyloidogenic Heptapeptides (23FGAILSS29)

“…The free energy profile is plotted by the following equation where P ( C ) is the probability distribution of the coordinate ( C ), P max is the maximum of the distribution, which is subtracted from P ( C ) to make Δ G = 0 for obtaining the lowest free energy minimum. 56 Two-dimensional free energy landscapes are projected onto the first two eigenvectors, V1 and V2, of the PCA. Basins that appear in the FEL plot generally belong to the conformations of oligomers that appear more during the simulation.…”