Amino acid bulkiness defines the local conformations and dynamics of natively unfolded alpha-synuclein and tau.

CHO, M.; KIM, H.; BERNADO, P.; FERNANDEZ, CO; BLACKLEDGE, M.; ZWECKSTETTER, M.

Journal of the American Chemical Society

Año: 2007 vol. 129 p. 3032 - 3033

0002-7863

Natively unfolded proteins play key roles in normal and pathological biochemical processes. The overall properties of unfolded proteins are similar to the random coil state and are rather insensitive to the details of the amino acid sequence. Spectroscopic measurements, however, suggest the presence of sequence-specific residual secondary and even tertiary structure in unfolded states of proteins. NMR residual dipolar couplings (RDCs) are particularly sensitive probes for the structure and dynamics of biomolecules. When confined in weakly aligning media, unfolded proteins display surprisingly variable RDCs as a function of position along the chain, possibly even encoding the native topology. More recently, it was shown that RDCs in denatured proteins can be predicted from ensembles of unfolded structures that were generated by using a self-avoiding statistical coil model, which was based on residue-specific propensities from loop regions of a folded protein database. In this work we have  shown that a much simpler model can also explain many aspects of the profile of RDCs in unfolded proteins: Amino acid bulkiness, the ratio of the side chain volume to its length, predicts clearly observable features reporting on the local conformational behavior of natively unfolded proteins, such as the 140-residue protein a-synuclein (aS). Our results demonstrated that, although various types of intramolecular interactions, such as electrostatic interactions and solvent interactions play important roles, simple considerations of the bulkiness of amino acids predicts a major component of diverse parameters dependent on the local conformation and dynamics of aS and other natively unfolded proteins. Deviations from this random coil behavior, as evidenced by RDCs in the N- and C-terminal domain of aS, can provide detailed insight into residual secondary structure and long-range transient interactions in weakly structured proteins. The local steric restrictions in the unfolded state can also bias the conformational search toward native-like elements and thereby reduce the Levinthal paradox.