Dissecting the Forces that Dominate Dimerization of the Nucleotide Binding Domains of ABCB1

Dániel Szöllősi, G. Szakács, Peter Chiba, Thomas Stockner

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

P-glycoprotein, also known as multidrug resistance protein 1 or ABCB1, can export a wide range of chemically unrelated compounds, including chemotherapeutic drugs. ABCB1 consists of two transmembrane domains that form the substrate binding and translocation domain, and of two cytoplasmic nucleotide binding domains (NBDs) that energize substrate transport by ATP binding and hydrolysis. ATP binding triggers dimerization of the NBDs, which switches the transporter from an inward facing to an outward facing transmembrane domain conformation. We performed MD simulations to study the dynamic behavior of the NBD dimer in the presence or absence of nucleotides. In the apo configuration, the NBDs were overall attractive to each other as shown in the potential of mean force profile, but the energy well was shallow and broad. In contrast, a sharp and deep energy minimum (∼−42 kJ/mol) was found in the presence of ATP, leading to a well-defined conformation. Motif interaction network analyses revealed that ATP stabilizes the NBD dimer by serving as the central hub for interdomain connections. Simulations showed that forces promoting dimerization are multilayered, dominated by electrostatic interactions between the nucleotide and conserved amino acids of the signature sequence and the Walker A motif. In addition, direct and water-bridged hydrogen bonds between NBDs provided conformation-defining interactions. Importantly, we characterized a largely unrecognized but essential contribution from hydrophobic interactions between the adenine moiety of the nucleotides and a hydrophobic surface of the X-loop to the stabilization of the nucleotide-bound NBD dimer. These hydrophobic interactions lead to a sharp energy minimum, thereby conformationally restricting the nucleotide-bound state.

Original languageEnglish
Pages (from-to)331-342
Number of pages12
JournalBiophysical Journal
Volume114
Issue number2
DOIs
Publication statusPublished - Jan 23 2018

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Dimerization
Nucleotides
Adenosine Triphosphate
P-Glycoprotein
Hydrophobic and Hydrophilic Interactions
Adenine Nucleotides
Static Electricity
Hydrogen
Amino Acid Sequence
Hydrolysis

ASJC Scopus subject areas

  • Biophysics

Cite this

Dissecting the Forces that Dominate Dimerization of the Nucleotide Binding Domains of ABCB1. / Szöllősi, Dániel; Szakács, G.; Chiba, Peter; Stockner, Thomas.

In: Biophysical Journal, Vol. 114, No. 2, 23.01.2018, p. 331-342.

Research output: Contribution to journalArticle

Szöllősi, Dániel ; Szakács, G. ; Chiba, Peter ; Stockner, Thomas. / Dissecting the Forces that Dominate Dimerization of the Nucleotide Binding Domains of ABCB1. In: Biophysical Journal. 2018 ; Vol. 114, No. 2. pp. 331-342.
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