Conformational entropy of alanine versus glycine in protein denatured states

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 8; pp. 2661 - 2666
• Main Authors: Scott, Kathryn A, Alonso, Darwin O.V, Sato, Satoshi, Fersht, Alan R, Daggett, Valerie
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.02.2007; National Acad Sciences
• Subjects: Alanine - chemistry; Alanine - genetics; Amino acids; Biochemistry; Biological Sciences; Datasets; Entropy; Free energy; Glycine - chemistry; Glycine - genetics; High temperature; Kinetics; Modeling; Models, Biological; Molecular structure; Mutation - genetics; Peptides; Peptides - chemistry; Protein Conformation; Protein Denaturation; Protein folding; Proteins - chemistry; Simulation; Solvents; Surface areas; Trajectories
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0611182104

The presence of a solvent-exposed alanine residue stabilizes a helix by 0.4-2 kcal·mol⁻¹ relative to glycine. Various factors have been suggested to account for the differences in helical propensity, from the higher conformational freedom of glycine sequences in the unfolded state to hydrophobic and van der Waals' stabilization of the alanine side chain in the helical state. We have performed all-atom molecular dynamics simulations with explicit solvent and exhaustive sampling of model peptides to address the backbone conformational entropy difference between Ala and Gly in the denatured state. The mutation of Ala to Gly leads to an increase in conformational entropy equivalent to [almost equal to]0.4 kcal·mol⁻¹ in a fully flexible denatured, that is, unfolded, state. But, this energy is closely counterbalanced by the (measured) difference in free energy of transfer of the glycine and alanine side chains from the vapor phase to water so that the unfolded alanine- and glycine-containing peptides are approximately isoenergetic. The helix-stabilizing propensity of Ala relative to Gly thus mainly results from more favorable interactions of Ala in the folded helical structure. The small difference in energetics in the denatured states means that the Φ-values derived from Ala [rightward arrow] Gly scanning of helices are a very good measure of the extent of formation of structure in proteins with little residual structure in the denatured state.