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Here, using computational methods, we assess the transfer free energies of the peptide backbone from water to two osmolyte solutions, 2 M urea and 2 M TMAO. 18 Thus, the free energy dependence of protein stability as a function of osmolyte concentration can be predicted if one assumes that the transfer free energies of solvent exposed sidechain and backbone groups on the native and denatured states are additive. Recent work corrected the previous measurements for the activities of the model compounds in solution and showed that the strength of the hydrophobic interactions do not change substantially on transfer to urea, and that urea's favorable interaction with the protein backbone is responsible for its denaturing ability. 16, 17 In that model, the thermodynamic interaction of the side chains with the urea solution gave rise to the long held concept of favorable urea interaction with hydrophobic groups as a driving force in urea's denaturation effect. The evaluation of group transfer free energy values defined the now classic Tanford model for urea-induced protein denaturation. 11, 12 This provides the basis of a universal mechanism for osmolyte-mediated protein stabilization by protecting osmolytes and destabilization by urea as the protein backbone is shared by all proteins, regardless of side chain sequence. Based on the transfer model and experimental Δ G tr for these groups it has been proposed that osmolytes exert their effect on protein stability primarily via the protein backbone. Transfer free energy values for sidechains and peptide backbone, Δ G tr, quantify the thermodynamic consequences of solvating a protein species in a cosolvent solution relative to pure water. 4, 5 The study of TMAO's properties has proved to be useful in providing insight into fundamental aspects of protein stability, as well as providing important concepts involving numerous diseases. TMAO prevents the denaturation of proteins in the presence of high intracellular concentrations of urea found in such organisms as marine elasmobranches. 2, 3Īn interesting example of the usage of osmolytes in nature is the counterbalance between the denaturing effects of urea and the protective ability of trimethylamine N-oxide (TMAO).
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1 The relationship between osmolytes and protein stability is biologically unique in that many protecting osmolytes have undergone natural selection not only for their effectiveness in regulating cell volume, but also for their ability to stabilize proteins against certain denaturing stresses. protecting osmolytes destabilize the unfolded state and facilitate protein folding, whereas the nonprotecting osmolyte urea stabilizes the unfolded state and denatures proteins. These small cosolvent molecules can have profound effects on protein stability, e.g. The study of the action of organic osmolytes on protein solutions has revealed many fundamental aspects of protein folding. The peptide backbone unit computed transfer free energy of −54 cal/mol/M compares quite favorably with −43 cal/mol/M determined experimentally. The simulations used here allow for the calculation of the solvation and transfer free energy of longer oligoglycine models to be evaluated than is currently possible through experiment. The peptide backbone transfer free energy contributions arise from van der Waals interactions in the case of transfer to urea, but from electrostatics on transfer to TMAO solution. The results show that the transfer free energies change linearly with increasing chain length, demonstrating the principle of additivity, and provide values in reasonable agreement with experiment. Solvation free energies of oligoglycine models of varying lengths in pure water and in the osmolyte solutions, 2 M urea and 2 M trimethylamine N-oxide (TMAO), were calculated from simulations of all atom models, and Δ G tr values for peptide backbone transfer from water to the osmolyte solutions were determined. Molecular dynamics simulations are used to determine the extent of change in transfer free energy (Δ G tr) with increase in chain length of oligoglycine with capped end groups. The transfer model implying additivity of the peptide backbone free energy of transfer is computationally tested.