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Abstract
Longstanding mechanistic questions about the role of protecting osmolyte trimethylamine
N- oxide (TMAO) which favors protein folding and the denaturing osmolyte urea are
addressed by studying their effects on the folding of uncharged polymer chains. Using
atomistic molecular dynamics simulations, we show that 1-M TMAO and 7-M urea solutions
act dramatically differently on these model polymer chains. Their behaviors are sensitive
to the strength of the attractive dispersion interactions of the chain with its environment:
when these dispersion interactions are high enough, TMAO suppresses the formation
of extended conformations of the hydrophobic polymer as compared to water, while urea
promotes formation of extended conformations. Similar trends are observed experimentally
on real protein systems. Quite surprisingly, we find that both protecting and denaturing
osmolytes strongly interact with the polymer, seemingly in contrast with existing
explanations of the osmolyte effect on proteins. We show that what really matters
for a protective osmolyte is its effective depletion as the polymer conformation changes,
which leads to a negative change in the preferential binding coefficient. For TMAO,
there is a much more favorable free energy of insertion of a single osmolyte near
collapsed conformations of the polymer than near extended conformations. By contrast,
urea is preferentially stabilized next to the extended conformation and thus has a
denaturing effect.