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.
Highlights
The conformational manifolds of unfolded and intrinsically disordered peptides and proteins are many times described by the random coil model, which assumes that amino acid residues sample the entire sterically accessible space of the dihedral angles φ and ψ in the Ramachandran plot with comparable probabilities [1,2,3,4]
The Gaussian model for glycine is comprised of three Gaussian sub-distributions corresponding to polyproline II (pPII), β, and right-handed helical mesostates alongside the corresponding sub-distributions on the right side of the Ramachandran space due to nonchiral nature of glycine reflected in the inversion symmetry of the Ramachandran distribution
The φ and ψ coordinates of the pPII and β sub-distributions are moved within certain intervals defined by the boundaries of the respective mesostate
Summary
The conformational manifolds of unfolded and intrinsically disordered peptides and proteins are many times described by the random coil model, which assumes that amino acid residues sample the entire sterically accessible space of the dihedral angles φ and ψ in the Ramachandran plot with comparable probabilities [1,2,3,4]. Deviations from the ideal random coil ensemble are generally believed to arise due to strong non-local interactions within compact or globular conformations or protein–solvent interactions in extended statistical coils [5,6,7] This view has been modified over the last twenty years due to overwhelming experimental evidence which demonstrates that amino acid residues in a water sample a much more restricted space of the Ramachandran space than expected based on the above considerations. Of all amino acid residues, alanine stands out by exhibiting a notoriously high pPII propensity with a mole fractions between 0.6 and 0.9 [14,17,18,19,20,21] This observation and distinct pPII propensities of guest amino acid residues x in unblocked GxG peptides and corresponding blocked dipeptides [11,19,22,23,24] suggest that the pPII preference may be associated with the side-chain characteristics [19,22,25]. Determining the Ramachandran distribution of glycine in a polyglycine, which ensures the absence of nearest-neighbor interactions, is pivotal for the understanding how side chains and solvent affect the conformational distribution of the peptide/protein backbone
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