College
College of Arts & Sciences
Mentor Information
Dr. Arjan van der Vaart
Description
Chameleon sequences and metamorphic proteins are prime examples of fold switchers, sequences that adopt more than one fold. This project addresses the refolding of a designed peptide from ɑ-helix to a β-pin by utilizing molecular dynamics and free-energy simulations. The goal is to reveal which amino acids are hotspots for refolding, as each amino acid has distinct chemical structure and folding propensity. We employed the confinement method, which involved progressive cycles of restrained simulations to convert the peptide to a harmonic oscillator, desolvation and removal of long-range electrostatics. Using the CHARMM 36 force field, the conformational free energy difference was calculated to be -55 +/- 1.9 kcal/mol, favoring the β-pin, which did not agree with experimental values. The source of this discrepancy may be the presence of glycine and two protonated histidines, which have low helical propensities. Continuing efforts to use other force fields to keep both folds stable are described. Completion of this project will identify factors that control protein structure and refolding, with relevance for chameleon sequences and metamorphic proteins.
Residue Hotspots for Peptide Refolding
Chameleon sequences and metamorphic proteins are prime examples of fold switchers, sequences that adopt more than one fold. This project addresses the refolding of a designed peptide from ɑ-helix to a β-pin by utilizing molecular dynamics and free-energy simulations. The goal is to reveal which amino acids are hotspots for refolding, as each amino acid has distinct chemical structure and folding propensity. We employed the confinement method, which involved progressive cycles of restrained simulations to convert the peptide to a harmonic oscillator, desolvation and removal of long-range electrostatics. Using the CHARMM 36 force field, the conformational free energy difference was calculated to be -55 +/- 1.9 kcal/mol, favoring the β-pin, which did not agree with experimental values. The source of this discrepancy may be the presence of glycine and two protonated histidines, which have low helical propensities. Continuing efforts to use other force fields to keep both folds stable are described. Completion of this project will identify factors that control protein structure and refolding, with relevance for chameleon sequences and metamorphic proteins.
