Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC6222333 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Zhou Yan Y Ojeda-May Pedro P Nagaraju Mulpuri M Kim Bryant B Pu Jingzhi J

Molecules (Basel, Switzerland) 20181016 10

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 <i>E. coli</i> HlyB may catalyze the hydrolysis of ATP through proton relay. To further test this hyp ...[more]

PMID: 30332773

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Project description:The nature and mechanism of phosphate hydrolysis reactions are of great interest in view of the crucial role of these reactions in key biological processes. Although it is becoming clearer that the ultimate way of resolving mechanistic controversies must involve reliable theoretical studies, it is not widely realized that such studies cannot be performed at present by using most existing automated ways and that only careful systematic studies can lead to meaningful conclusions. The present work clarifies the above point by considering the hydrolysis of phosphate monoesters. The clarification starts by defining the actual issues that should be addressed in careful studies and by highlighting the problems with studies that ignore the need for unique mechanistic definitions (e.g., works that confuse associative and dissociative pathways). We then focus on the analysis of the proton transfer (PT) pathways in phosphate hydrolysis and on recent suggestions that PT involves more than one water molecule. Here we point out that most of the studies that found a proton transfer through several water molecules have not involved a sufficient systematic search of the relevant reaction coordinates. This includes both energy minimization approaches as well as a recent metadynamics (MTD) simulation study. To illustrate the crucial need of exploring the potential surfaces reliably, rather than relying on automated approaches, we present here a very careful study of the free energy landscape along a 3D reaction coordinate (RC) exploring both the standard 2D RC, comprised of the attacking and leaving group reaction coordinates, as well as of the proton transfer (PT) coordinate. Our study points out that QM/MM minimization or MTD studies that concluded that the hydrolysis of phosphate monoesters involves a PT through several water molecules, have not explored carefully the single water (1W) path (that involves a direct PT form the attacking water molecule to the phosphate oxygen). Furthermore, we identified the most likely reason for the difficulty in finding the 1W path by QM/MM minimization methods, as well as by the current MTD simulations. We also discuss the problems with current studies that challenge the phosphate as a base mechanism and emphasize that all recent studies found associative/concerted paths (although many have not realized the meaning of their results). Finally, although we clearly do not have the last word about the 1W versus 2W paths we believe that we illustrated that the crucial mechanistic problems with alternative pathways should not be resolved by just running black box search approaches.

Dataset Information

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

Publications

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

Similar Datasets

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