Modelling the free energy profile of the mitochondrial ADP/ATP carrier.
Biochimica et biophysica acta. Bioenergetics
MetadataShow full item record
Springett, R., King, M., Crichton, P. G., & Kunji, E. (2017). Modelling the free energy profile of the mitochondrial ADP/ATP carrier.. Biochimica et biophysica acta. Bioenergetics, 1858 (11), 906-914. https://doi.org/10.1016/j.bbabio.2017.05.006
The mitochondrial ADP/ATP carrier catalyses the equimolar exchange of adenosine di- and tri-phosphates. It operates by an alternating access mechanism in which a single substrate-binding site is made available either to the mitochondrial matrix or the intermembrane space through conformational changes. These changes are prevented in the absence of substrate by a large energy barrier due to the need for sequential disruption and formation of a matrix and cytoplasmic salt bridge network that are located on either side of the central cavity. In analogy to enzyme catalysis, substrate lowers the energy barrier by binding tighter in the intermediate state. Here we provide an in-silico kinetic model that captures the free energy profile of these conformational changes and treats the carrier as a nanomachine moving stochastically from the matrix to cytoplasmic conformation under the influence of thermal energy. The model reproduces the dependency of experimentally determined kcat and KM values on the cytoplasmic network strength with good quantitative accuracy, implying that it captures the transport mechanism and can provide a framework to understand the structure-function relationships of this class of transporter. The results show that maximum transport occurs when the interaction energies of the cytoplasmic network, matrix network and substrate binding are approximately equal such that the energy barrier is minimized. Consequently, the model predicts that there will be other interactions in addition to those of the cytoplasmic network that stabilise the matrix conformation of the ADP/ATP carrier.
Mitochondria, Lactococcus lactis, Saccharomycetales, Mitochondrial ADP, ATP Translocases, Fungal Proteins, Recombinant Proteins, Adenosine Diphosphate, Adenosine Triphosphate, Cloning, Molecular, Gene Expression, Kinetics, Thermodynamics
External DOI: https://doi.org/10.1016/j.bbabio.2017.05.006
This record's URL: https://www.repository.cam.ac.uk/handle/1810/265978
Recommended or similar items
The following licence files are associated with this item: