Effects of Ligand Binding on the Energy Landscape of Acyl-CoA-Binding Protein.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
03 11 2020
03 11 2020
Historique:
received:
15
05
2020
revised:
14
08
2020
accepted:
08
09
2020
pubmed:
21
10
2020
medline:
15
5
2021
entrez:
20
10
2020
Statut:
ppublish
Résumé
Binding of ligands is often crucial for function yet the effects of ligand binding on the mechanical stability and energy landscape of proteins are incompletely understood. Here, we use a combination of single-molecule optical tweezers and MD simulations to investigate the effect of ligand binding on the energy landscape of acyl-coenzyme A (CoA)-binding protein (ACBP). ACBP is a topologically simple and highly conserved four-α-helix bundle protein that acts as an intracellular transporter and buffer for fatty-acyl-CoA and is active in membrane assembly. We have previously described the behavior of ACBP under tension, revealing a highly extended transition state (TS) located almost halfway between the unfolded and native states. Here, we performed force-ramp and force-jump experiments, in combination with advanced statistical analysis, to show that octanoyl-CoA binding increases the activation free energy for the unfolding reaction of ACBP without affecting the position of the transition state along the reaction coordinate. It follows that ligand binding enhances the mechanical resistance and thermodynamic stability of the protein, without changing its mechanical compliance. Steered molecular dynamics simulations allowed us to rationalize the results in terms of key interactions that octanoyl-CoA establishes with the four α-helices of ACBP and showed that the unfolding pathway is marginally affected by the ligand. The results show that ligand-induced mechanical stabilization effects can be complex and may prove useful for the rational design of stabilizing ligands.
Identifiants
pubmed: 33080224
pii: S0006-3495(20)30727-X
doi: 10.1016/j.bpj.2020.09.016
pmc: PMC7677128
pii:
doi:
Substances chimiques
Diazepam Binding Inhibitor
0
Ligands
0
Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1821-1832Informations de copyright
Copyright © 2020 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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