Glycine in Water Favors the Polyproline II State

Abstract

Conformational preferences of amino acid residues in water are determined by the backbone and side-chain properties. Alanine is known for its high polyproline II (pPII) propensity. The question of relative contributions of the backbone and side chain to the conformational preferences of alanine and other amino acid residues in water is not fully resolved. Because glycine lacks a heavy-atom side chain, glycine-based peptides can be used to examine to which extent the backbone properties affect the conformational space. Here, we use published spectroscopic data for the central glycine residue of cationic triglycine in water to demonstrate that its conformational space is dominated by the pPII state. We assess three commonly used molecular dynamics (MD) force fields with respect to their ability to capture the conformational preferences of the central glycine residue in triglycine. We show that pPII is the mesostate that enables the functional backbone groups of the central residue to form the most hydrogen bonds with water. Our results indicate that the pPII propensity of the central glycine in GGG is comparable to that of alanine in GAG, implying that the water-backbone hydrogen bonding is responsible for the high pPII content of these residues.

Do molecular dynamics force fields accurately model Ramachandran distributions of amino acid residues in water?

“…28 The results revealed that pPII is driven by the tendency of water to maximize the number of hydrogen bonds between water and the functional groups of the central glycine, demonstrating that high pPII preference of amino acid residues stems from the water-backbone interactions. 28 Interestingly, Amber ff14SB was outperformed by the other two force fields with respect to its capacity to capture conformational dynamics of glycine residue in water. 28 Several recent studies revealed that CHARMM36m combined with its specialized TIP3P water model performs better than the other additive force fields, although there is still room for improvement.…”

“…26 A follow-up study, Andrews et al asked whether alanine's preference for the pPII state stems from the backbone or alanine's side chain characteristics. 28 To this end, the experiment-based Gaussian modeling was applied to the central glycine residue in cationic GGG as a model of a peptide backbone, followed by the corresponding assessment of Amber ff14SB (with TIP3P), OPLS-AA/M (with TIP4P), and CHARMM36m (with the respective TIP3P model). 28 The results revealed that pPII is driven by the tendency of water to maximize the number of hydrogen bonds between water and the functional groups of the central glycine, demonstrating that high pPII preference of amino acid residues stems from the water-backbone interactions.…”

“…28 To this end, the experiment-based Gaussian modeling was applied to the central glycine residue in cationic GGG as a model of a peptide backbone, followed by the corresponding assessment of Amber ff14SB (with TIP3P), OPLS-AA/M (with TIP4P), and CHARMM36m (with the respective TIP3P model). 28 The results revealed that pPII is driven by the tendency of water to maximize the number of hydrogen bonds between water and the functional groups of the central glycine, demonstrating that high pPII preference of amino acid residues stems from the water-backbone interactions. 28 Interestingly, Amber ff14SB was outperformed by the other two force fields with respect to its capacity to capture conformational dynamics of glycine residue in water.…”

Short peptides as predictors for the structure of polyarginine sequences in disordered proteins

“…Stoichiometric amounts of Clatoms are added to ensure electroneutrality. Each 500 ns long trajectory is acquired using the velocity rescale thermostat 25 and the Berendsen barostat. 26 In order to assess the MD-based Ramachandran distributions we calculated the occupation of mesostates that cover populated regions of the Ramachandran plot.…”

“…Backbone and side chain interactions with the solvent cause the intrinsic conformational propensities of amino acids to differ significantly. [23][24][25][26] Residues preferably sample the upper left quadrant of the Ramachandran plot (between 70 and 80%). [27][28][29][30][31] The remaining 20-30% are generally distributed over several turn-like conformations.…”