Abstract
The denatured state of several proteins has been shown to display
transient structures that are relevant for folding, stability and
aggregation. To detect them by nuclear magnetic resonance (NMR)
spectroscopy, the denatured state must be stabilized by chemical agents
or changes in temperature. This makes the environment different from
that experienced in biologically relevant processes. Using
high-resolution heteronuclear NMR spectroscopy, we have characterized
several denatured states of a monomeric variant of HIV-1 protease
induced by different concentrations of urea, guanidinium chloride and
acetic acid. We have extrapolated the chemical shifts and the relaxation
parameters to the denaturant-free denatured state at native conditions,
showing that they converge to the same values. Subsequently, we
characterized the conformational properties of this biologically
relevant denatured state under native conditions by advanced molecular
dynamics simulations and validated the results by comparison to
experimental data. We show that the denatured state of HIV-1 protease
under native conditions displays rich patterns of transient native and
non-native structures, which could be of relevance to its guidance
through a complex folding process.