TY - JOUR
T1 - A Computational Study of the Ionic Liquid-Induced Destabilization of the Miniprotein Trp-Cage
AU - Uralcan, Betul
AU - Kim, Sang Beom
AU - Markwalter, Chester E.
AU - Prud'Homme, Robert K.
AU - Debenedetti, Pablo G.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/5/31
Y1 - 2018/5/31
N2 - Fundamental understanding of protein stability away from physiological conditions is important due to its evolutionary implications and relevance to industrial processing and storage of biological materials. The molecular mechanisms of stabilization/destabilization by environmental perturbations are incompletely understood. We use replica-exchange molecular dynamics simulations and thermodynamic analysis to investigate the effects of ionic liquid-induced perturbations on the folding/unfolding thermodynamics of the Trp-cage miniprotein. We find that ionic liquid-induced denaturation resembles cold unfolding, where the unfolded states are populated by compact, partially folded structures in which elements of the secondary structure are conserved, while the tertiary structure is disrupted. Our simulations show that the intrusion of ions and water into Trp-cage's hydrophobic core is facilitated by the disruption of its salt bridge and 310-helix by specific ion-residue interactions. Despite the swelling and widening of the hydrophobic core, however, Trp-cage's α-helix remains stable. We further show that ionic liquid disrupts protein-protein and protein-water hydrogen bonds while favoring the formation of ion-protein bonds, shifting the equilibrium of conformational states and promoting denaturation near room temperature.
AB - Fundamental understanding of protein stability away from physiological conditions is important due to its evolutionary implications and relevance to industrial processing and storage of biological materials. The molecular mechanisms of stabilization/destabilization by environmental perturbations are incompletely understood. We use replica-exchange molecular dynamics simulations and thermodynamic analysis to investigate the effects of ionic liquid-induced perturbations on the folding/unfolding thermodynamics of the Trp-cage miniprotein. We find that ionic liquid-induced denaturation resembles cold unfolding, where the unfolded states are populated by compact, partially folded structures in which elements of the secondary structure are conserved, while the tertiary structure is disrupted. Our simulations show that the intrusion of ions and water into Trp-cage's hydrophobic core is facilitated by the disruption of its salt bridge and 310-helix by specific ion-residue interactions. Despite the swelling and widening of the hydrophobic core, however, Trp-cage's α-helix remains stable. We further show that ionic liquid disrupts protein-protein and protein-water hydrogen bonds while favoring the formation of ion-protein bonds, shifting the equilibrium of conformational states and promoting denaturation near room temperature.
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U2 - 10.1021/acs.jpcb.8b01722
DO - 10.1021/acs.jpcb.8b01722
M3 - Article
C2 - 29617131
AN - SCOPUS:85048076721
SN - 1520-6106
VL - 122
SP - 5707
EP - 5715
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 21
ER -