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Open AccessFeature PaperArticle

Mapping Free Energy Pathways for ATP Hydrolysis in the E. coli ABC Transporter HlyB by the String Method

Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 N. Blackford St., LD326, Indianapolis, IN 46202, USA
*
Author to whom correspondence should be addressed.
Current address: Department of Chemistry, Guangxi University for Nationalities, Nanning 530000, China.
Current address: High Performance Computing Center North (HPC2N), Umeå University, SE-901-87 Umeå, Sweden.
Molecules 2018, 23(10), 2652; https://doi.org/10.3390/molecules23102652
Received: 8 September 2018 / Revised: 9 October 2018 / Accepted: 10 October 2018 / Published: 16 October 2018
HlyB functions as an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that enables bacteria to secrete toxins at the expense of ATP hydrolysis. Our previous work, based on potential energy profiles from combined quantum mechanical and molecular mechanical (QM/MM) calculations, has suggested that the highly conserved H-loop His residue H662 in the nucleotide binding domain (NBD) of E. coli HlyB may catalyze the hydrolysis of ATP through proton relay. To further test this hypothesis when entropic contributions are taken into account, we obtained QM/MM minimum free energy paths (MFEPs) for the HlyB reaction, making use of the string method in collective variables. The free energy profiles along the MFEPs confirm the direct participation of H662 in catalysis. The MFEP simulations of HlyB also reveal an intimate coupling between the chemical steps and a local protein conformational change involving the signature-loop residue S607, which may serve a catalytic role similar to an Arg-finger motif in many ATPases and GTPases in stabilizing the phosphoryl-transfer transition state. View Full-Text
Keywords: QM/MM; free energy simulations; ABC transporter; ATP hydrolysis; string method; minimum free energy path; proton transfer QM/MM; free energy simulations; ABC transporter; ATP hydrolysis; string method; minimum free energy path; proton transfer
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MDPI and ACS Style

Zhou, Y.; Ojeda-May, P.; Nagaraju, M.; Kim, B.; Pu, J. Mapping Free Energy Pathways for ATP Hydrolysis in the E. coli ABC Transporter HlyB by the String Method. Molecules 2018, 23, 2652.

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