Molecular dynamics analysis of the conformations of a β-hairpin miniprotein

Molecular dynamics simulations of a β-hairpin miniprotein, CLN025, were performed to examine the conformational stability of the peptide in H ₂O at 278, 300, 333, and 363 K, as well as in TFE, MeOH, and DMSO at 300 K. CLN025 is a variant of the Chignolin miniprotein, in which the terminal Gly residues of Chignolin are replaced with Tyr residues, which leads to a 29.7 K increase in melting temperature. The energy of the intramolecular interactions was calculated using DFT quantum chemical calculations at the BHandHLYP/cc-pVTZ level of theory. CLN025 maintained a β-hairpin conformation in all environments. The β-hairpin is stabilized by hydrogen bonds, an electrostatic interaction between the charged termini of the peptide, and weakly polar interactions. The interaction between the backbones of the N and C-terminal strands accounts for -97.32 to -120.87 kcal mol^-1 of the stabilization energy. The energies of the CH-π interactions between Tyr2 and Pro4 were between -1.80 and -8.9 kcal mol^-1, and the energy of the Tyr2-Trp9 Ar-Ar interaction was between -0.43 and -8.11 kcal mol^-1. Increasing temperature caused the Tyr2-Pro4 CH-π and the Tyr2-Trp9 and Tyr2-Tyr10 Ar-Ar interactions to become less favorable, but the Tyr1-Trp9 interaction became more favorable and played an important role in stabilizing the β-hairpin of CLN025 that resulted in the increased melting temperature. Weakly polar interactions play an important role in the structure and stability of CLN025 and other proteins.