Contribution of proline to the pre-structuring tendency of transient helical secondary structure elements in intrinsically disordered proteins

Intrinsically Disordered Proteins: Where Computation Meets Experiment

“…Their simulations revealed that substitution of N-terminal prolines for other amino acids decreases the amount of helicity within the pre-structured motifs, and substitution of C-terminal prolines for other amino acids increases the amount of helicity within the pre-structured motifs. Based on these findings, Lee et al argued that the location of prolines in regions flanking pre-structured motifs may have evolved to control the degree of pre-formed helicity within disordered regions, thereby regulating the degree of conformational selection by IDP partners [130]. Recently, Szöllősi et al used molecular simulations to predict a number of pre-formed regions across a large set of IDPs [131], including the MDM2-binding region in p53.…”

“…For example, three pre-structured motifs have been detected in p53 TAD with NMR spectroscopy: a helix located in residues 18-26 and predicted to be present in 20% of the unbound population; a turn located in residues 40-44 that is predicted to be present in 5% of the population; and a turn in residues 48-53 that is predicted to be present in 15% of the population [126,129,130]. Each of these regions is flanked by a proline residue at the N-terminus and the C-terminus [130]. Prolines are known to terminate or cause kinks in helices, in part due to the phi/psi angles that they preferentially adopt in solution.…”

“…The studies discussed above for p53 TAD [125,[130][131][132] investigate the role of conformational selection in p53 IDRs using truncated p53 peptides. While the computational expense of these calculations often necessitate the use of short constructs and relatively short simulations times, it is important to recognize that the system of interest is the full-length protein.…”

“…Lee et al observed that prolines are enhanced in regions flanking pre-structured motifs in IDPS, and used molecular dynamics simulations to investigate the role of prolines in these regions [130]. They generated short (10 ns) MD simulations of the wild-type peptides and mutants in which the flanking prolines were substituted with aspartic acid, histidine, alanine, or lysine [130]. Their simulations revealed that substitution of N-terminal prolines for other amino acids decreases the amount of helicity within the pre-structured motifs, and substitution of C-terminal prolines for other amino acids increases the amount of helicity within the pre-structured motifs.…”

“…Prolines are known to terminate or cause kinks in helices, in part due to the phi/psi angles that they preferentially adopt in solution. Lee et al observed that prolines are enhanced in regions flanking pre-structured motifs in IDPS, and used molecular dynamics simulations to investigate the role of prolines in these regions [130]. They generated short (10 ns) MD simulations of the wild-type peptides and mutants in which the flanking prolines were substituted with aspartic acid, histidine, alanine, or lysine [130].…”