Probing the role of electrostatics of polypeptide main-chain in protein folding by perturbing N-terminal residue stereochemistry: DFT study with oligoalanine models

摘要

Expression of the genome rests primarily on proteins adopting folds in the specificity of their sequence code over side-chains. The underlying basis, despite intense scrutiny of the apparent code, remains largely unclear as a protein-folding problem. The interactions internal to the polypeptide main-chain are ubiquitous to folding but their contribution to the energetics of folding remains uncertain. Given the uncertain roles of the solvent and sequence, and uncertain energetics of folded proteins, simple models are required to study the interactions between the backbone peptide units of polypeptide main-chain by exclusion of solvent and sequence effects. Thus, the oligoalanine peptides Ac-(L)Ala(4)-NHMe (Ia), Ac-(D)Ala-(L)Ala(3)-NHMe (Ib), Ac-(L)Pro-(L)Ala(3)-NHMe (IIa), Ac-(D)Pro-(L)Ala(3)-NHMe (IIb), Ac-(L)Pro(2)-(L)Ala(2)-NHMe (IIIa) and Ac-(D)Pro-(L)Pro-(L)Ala(2)-NHMe (IIIb) were chosen as the N-terminal alanine or proline and L-or D-residue stereochemically perturbed models to scrutinize the role of electrostatics of backbone peptide units on the energetics of folding with density functional theory (DFT). DFT calculations revealed that the end-protected tetraalanine isomers, Ia and Ib, fold to identical specificity in hydrogen bonds, but with a strong contrast of energetics. Ib with a DLLL-stereochemical structure folds with apparent strength of hydrogen bonds twofold than Ia without, surprisingly, a notable change in geometry of the interactions involved. DFT calculations demonstrated that the energetics of folding from the extended structure to the folded structure in oligoalanine peptides critically depend on the geometrical relationship between backbone peptide units of the polypeptide structure. The results of the present study will provide key insights into the protein-folding problem and helix stability.