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Updated: Sep 13, 2025
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Chemical Modification of the Tryptophan Residue in a Recombinant Ca2+-ATPase N-domain for Studying Tryptophan-ANS FRET
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Molecular insights into ATP-mediated NBD dimerization in an ABC transporter
Vinothini Santhakumar1, Nahren Manuel Mascarenhas1
1Department of Chemistry, Sacred Heart College (Affiliated to Thiruvalluvar University, Vellore), Tirupattur District, Tamilnadu 635601, India.
Computational Biology and Chemistry
|July 27, 2025
Summary
ATP binding stabilizes the Cyanidioschyzon merolae ABCB1 transporter, promoting crucial salt-bridge interactions. This stabilization is key for substrate transport and conformational changes in ATP-binding cassette (ABC) transporters.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Dynamics
Background:
- CmABCB1, a homolog of human ABCB1, is an ATP-binding cassette (ABC) transporter.
- ABC transporters mediate substrate efflux via inward-facing and outward-facing conformations.
- Understanding ATP's role is crucial for elucidating transporter function.
Purpose of the Study:
- To investigate the influence of ATP binding on CmABCB1 dynamics and conformation.
- To determine the free energy of nucleotide-binding domain (NBD) interactions with and without ATP.
Main Methods:
- 1000-ns all-atom molecular dynamics (MD) simulations of CmABCB1 with and without ATP.
- Umbrella sampling (US) simulations to calculate NBD dimer binding free energy.
Main Results:
- MD simulations revealed significant structural differences based on ATP presence.
- A key salt-bridge interaction between the coupling helix (CH) and NBD was observed only with ATP.
- ATP binding was found to stabilize the NBD dimer by approximately 25 kJ/mol.
Conclusions:
- ATP binding is essential for specific CH-NBD interactions, potentially driving the conformational change to the outward-facing state.
- ATP significantly stabilizes the NBD dimer, impacting transporter function.
- Findings offer critical insights into the ATP-dependent transport cycle of ABC transporters.
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