Role of Backbone−Solvent Interactions in Determining Conformational Equilibria of Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) are functional proteins that do not fold into well-defined three-dimensional structures under physiological conditions. IDP sequences have low hydrophobicity, and hence, recent experiments have focused on quantitative studies of conformational ensembles of archetypal IDP sequences such as polyglutamine and glycine-serine block copolypeptides. Results from these experiments show that, despite the absence of hydrophobic residues, polar IDPs prefer ensembles of collapsed structures in aqueous milieus. Do these preferences originate in interactions that are unique to polar sidechains? The current study addresses this issue by analyzing conformational equilibria for polyglycine and a glycine-serine block copolypeptide in two environments, namely, water and 8 M urea. Polyglycine, a poly secondary-amide, has no sidechains and is a useful model system for generic polypeptide backbones. Results based on large-scale molecular dynamics simulations show that polyglycine forms compact, albeit disordered, globules in water and swollen, disordered coils in 8 M urea. There is minimal overlap between conformational ensembles in the two environments. Analysis of order parameters derived from theories for flexible polymers show that water at ambient temperatures is a poor solvent for generic polypeptide backbones. Therefore, the experimentally observed preferences for polyglutamine and glycine-serine block copolypeptides must originate, at least partially, in polypeptide backbones. A preliminary analysis of the driving forces that lead to distinct conformational preferences for polyglycine in two different environments is presented. Implications for describing conformational ensembles of generic IDP sequences are also discussed.

Backbone additivity in the transfer model of protein solvation

“…For each model, the total solvation free energy in TMAO solution is the most unfavorable solution environment (greatest free energy value), whereas the urea solution is the most favorable (lowest free energy). This is consistent with the notion that urea creates a better solution environment for the peptide backbone, [21][22][23] whereas TMAO is a poorer solvent than water. 19 Components analysis of the total solvation free energy allows for a mechanistic view of the thermodynamic effect of osmolyte solution on the solvation of the peptide backbone.…”

“…In the literature, we find a scatter of results from different models. Some previous simulations show urea hydrogen bonding with the peptide carbonyl group, 22,44,45 whereas others see more significant hydrogen bonding with the peptide amides as opposed to the peptide carbonyl group. 46 To provide a further description of the nature of osmolyte and backbone correlations, we have calculated the solvent density profile around the peptide.…”

“…In addition to this increased contact with the peptide backbone by urea, these collisions occur for longer periods of time, indicating stronger correlations. Several previous simulations have demonstrated the direct interaction of urea with peptide or protein 22,45,46,[50][51][52] as well as the lack of interaction between TMAO and a cyclic 53 and long peptide backbone model. 38 Similarly, solution hydrogen bonds with the peptide backbone models demonstrate very little hydrogen bonding of TMAO with the peptide backbone, whereas urea forms about 1/2 hydrogen bond per glycine residue.…”

“…Urea provides a better solvent environment for the peptide backbone, giving a computed transfer free of À54 cal/mol/M that compares quite favorably with À43 cal/mol/M determined experimentally. [21][22][23] Similarly, the presence of TMAO creates a more unfavorable environment for enhanced water solvation of the peptide backbone and it strongly interacts with water, normally crystallizing as a dihydrate. All this makes TMAO a comparatively poor solvent for the peptide backbone.…”

“…We see the denaturing osmolyte acting as a hydrogen bond donor with far more frequency than as a hydrogen bond acceptor. 22,39 Methods Each peptide backbone was created in its extended conformation using the CHARMM-27 all atom parameter set 41 and subjected to energy minimization using the steepest descent method. The osmolyte solutions consisted of 66 osmolyte molecules and 1614 TIP3P 54 water molecules in a cubic simulation box with lengths of 3.8 nm, resulting in 2M osmolyte concentration.…”