Protein structures are dynamic and can explore a large conformational landscape1,2. Only some of these structural substates are important for protein function (i.e. ligand binding, catalysis and regulation)3–5. How evolution shapes the structural ensemble to optimize a specific function is poorly understood>3,4. One of the constraints on the evolution of proteins is the stability of the folded ‘native’ state. Despite this, 44% of the human proteome contains intrinsically disordered (ID) peptide segments >30 residues in length6, the majority of which have no known function7–9. Here we show that the entropic force produced by an ID carboxy-terminus (ID-tail) shifts the conformational ensemble of human UDP-α-D-glucose-6-dehydrogenase (hUGDH) toward a substate with a high affinity for an allosteric inhibitor. The function of the ID-tail does not depend on its sequence or chemical composition. Instead, the affinity enhancement can be accurately predicted based on the length of the ID segment and is consistent with the entropic force generated by an unstructured peptide attached to the protein surface10–13. Our data show that the unfolded state of the ID-tail rectifies the dynamics and structure of hUGDH to favor inhibitor binding. Because this entropic rectifier does not have any sequence or structural constraints, it is an easily acquired adaptation. This model implies that evolution selects for disordered segments to tune the energy landscape of proteins, which may explain the persistence of ID in the proteome.

Yeast phenylalanine transfer RNA was subjected to a 12-picosecond molecular dynamics simulation. The principal features of the x-ray crystallographic analysis are reproduced, and the amplitudes of atomic displacements appear to be determined by the degree of exposure of the atoms. An analysis of the hydrogen bonds shows a correlation between the average length of a bond and the fluctuation in that length and reveals a rocking motion of bases in Watson-Crick guanine X cytosine base pairs. The in-plane motions of the bases are generally of larger amplitude than the out-of-plane motions, and there are correlations in the motions of adjacent bases.

SynopsisThe atomic motions from a molecular-dynamics simulation of yeast tRNAPhe are analyzed and compared with those observed in protein simulations. In general, the tRNA motions are of larger amplitude, they are more anisotropic, and they arise from potentials of mean force that are more anharmonic than in the protein case. In both cases, the amplitudes are largest for atoms on the surface of the molecules. On the other hand, the most anisotropic and anharmonic atomic motions are generally found in the interior of the tRNA, while they are found on the surface of the protein. These differences are discussed in terms of the differences in structure between nucleic acids and proteins.

SynopsisA 24-ps moleculardynamics simulation of motions in yeast tRNAPhe has been completed. The overall structure of the molecule is well preserved, for the motions represent fluctuations about an average structure that is very much like the crystallographic structure. The four helical stems remain intact, the structures of the loop regions do not deteriorate, and even the base stacking in the single-stranded amino acid acceptor terminus is maintained. With two exceptions, none of the sugar puckers is significantly changed. The unconstrained floppy motions of base A76 are responsible for the repuckering of ribose 76. The other sugar that repuckers is ribose 46, and this is the result of a very small structural change in the center of the molecule that is also responsible for the breakage of one tertiary hydrogen bond. This change in local structure does not seriously distort the base-stacking and intercalation patterns where the variable loop and the D-stem interact.