Electrostatic funneling of substrate in mitochondrial inner membrane carriers

Research output: Contribution to journalArticle

Abstract

Exchange of ATP and ADP across mitochondrial membrane replenishes the cytoplasm with newly synthesized ATP and provides the mitochondria with the substrate ADP for oxidative phosphorylation. The sole means of this exchange is the mitochondrial ADP/ATP carrier (AAC), a membrane protein that is suggested to cycle between two conformationally distinct states, cytosolic-open (c-state) and matrix-open (m-state), thereby shuttling nucleotides across the inner mitochondrial membrane. However, the c-state is the only structurally resolved state, and the binding site of ADP remains elusive. Here, we present ≈0.3 μs of all-atom MD simulations of the c-state revealing rapid, spontaneous binding of ADP to deeply positioned binding sites within the AAC lumen. To our knowledge, a complete ligand-binding event has heretofore not been described in full atomic detail in unbiased simulations. The identified ADP-bound state and additional simulations shed light on key structural elements and the initial steps involved in conversion to the m-state. Electrostatic analysis of trajectories reveals the presence of an unusually strong positive electrostatic potential in the lumen of AAC that appears to be the main driving force for the observed spontaneous binding of ADP. We provide evidence that the positive electrostatic potential is likely a common attribute among the entire family of mitochondrial carriers. In addition to playing a key role in substrate recruitment and translocation, the electropositivity of mitochondrial carriers might also be critical for their binding to the negatively charged environment of the inner mitochondrial membrane.

Original languageEnglish (US)
Pages (from-to)9598-9603
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number28
DOIs
StatePublished - Jul 15 2008

Keywords

  • ADP/ATP carrier
  • Ligand binding
  • Mitochondrial carrier family
  • Molecular dynamics
  • Nucleotide translocation

ASJC Scopus subject areas

  • General

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