Topology, landscapes, and biomolecular energy transport

Elenewski, Justin E.; Velizhanin, Kirill A.; Zwolak, Michael

doi:10.1038/s41467-019-12700-w

Cited by 8 publications

(4 citation statements)

References 56 publications

(86 reference statements)

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“…Catalysis-fueled propulsion of biomolecules at the nanoscale is no doubt a fascinating concept and has potential applications in the field of nanoscience and medicine ( 42 – 49 ). However, mounting experimental and theoretical evidence argue against the mechanism, scale, and even the existence of such phenomenon ( 1 , 2 , 14 , 16 , 38 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

Single-molecule diffusometry reveals no catalysis-induced diffusion enhancement of alkaline phosphatase as proposed by FCS experiments

Chen

Shaw

Wilson

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Theoretical and experimental observations that catalysis enhances the diffusion of enzymes have generated exciting implications about nanoscale energy flow, molecular chemotaxis, and self-powered nanomachines. However, contradictory claims on the origin, magnitude, and consequence of this phenomenon continue to arise. To date, experimental observations of catalysis-enhanced enzyme diffusion have relied almost exclusively on fluorescence correlation spectroscopy (FCS), a technique that provides only indirect, ensemble-averaged measurements of diffusion behavior. Here, using an anti-Brownian electrokinetic (ABEL) trap and in-solution single-particle tracking, we show that catalysis does not increase the diffusion of alkaline phosphatase (ALP) at the single-molecule level, in sharp contrast to the ∼20% enhancement seen in parallel FCS experiments using p-nitrophenyl phosphate (pNPP) as substrate. Combining comprehensive FCS controls, ABEL trap, surface-based single-molecule fluorescence, and Monte Carlo simulations, we establish that pNPP-induced dye blinking at the ∼10-ms timescale is responsible for the apparent diffusion enhancement seen in FCS. Our observations urge a crucial revisit of various experimental findings and theoretical models––including those of our own––in the field, and indicate that in-solution single-particle tracking and ABEL trap are more reliable means to investigate diffusion phenomena at the nanoscale.

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Section: Discussionmentioning

confidence: 99%

Single-molecule diffusometry reveals no catalysis-induced diffusion enhancement of alkaline phosphatase as proposed by FCS experiments

Chen

Shaw

Wilson

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Vibrational energy transport through biomolecules continues to be the focus of experimental and computational study, − with much attention given to the role of nonbonded contacts, in some cases with water molecules, in energy transport. While contacts that mediate energy transfer locally depend of course on the structures sampled by the biomolecule over times during which energy transport occurs, several studies also reveal the role of contact fluctuations in energy transfer, and a relation between rates of energy transfer and equilibrium structural fluctuations has been identified, ,, which has been studied computationally mainly for polar contacts between residues.…”

Section: Introductionmentioning

confidence: 99%

Variation of Energy Transfer Rates across Protein–Water Contacts with Equilibrium Structural Fluctuations of a Homodimeric Hemoglobin

2020

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Molecular dynamics simulations of the homodimeric hemoglobin from Scapharca inaequivalvis (HbI) have been carried out to examine relations between rates of vibrational energy transfer across nonbonded contacts and equilibrium structural fluctuations, with emphasis on protein−water contacts. The scaling of rates of energy transfer with equilibrium fluctuations of the contact length is found to hold up well for contacts between residues and hemes at the interface and the cluster of 17 interface water molecules in the unliganded state of HbI, as well as for the liganded state, for which the cluster contains on average 11 water molecules. In both states, the rate of energy transfer is also found to satisfy a diffusion relation. Within each globule, the scaling for polar contacts is similar to that found in an earlier analysis of myoglobin. Entropy associated with dynamics of polar contacts within each globule and with contacts between the hemes and water cluster is found to increase upon ligation. Energy exchange networks (EENs) for liganded and unliganded states obtained from the simulations are also presented and discussed. Energy transport networks through which nonbonded contacts transport energy in HbI, referred to as nonbonded networks (NBNs), are determined from the EENs and compared for the two states.

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“…To rigorously compare the simulated protein-membrane interactions of VLCAD and its proline-mutant variants, we performed quantitative analyses using a series of geometric parameters. Using a collective variable hlx 32 , which captures the relative helical content of a polymer and serves as an order parameter for the helix-coil transition 33,34 , we found that the α-helical character of C-terminal residues 436-488 in the wild-type protein remained high throughout the simulation, whereas the α-helical content of the corresponding region in the A450P and L462P variants was markedly decreased during the initial equilibration (Fig. 5f).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency

et al. 2022

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Very long-chain acyl-CoA dehydrogenase (VLCAD) is an inner mitochondrial membrane enzyme that catalyzes the first and rate-limiting step of long-chain fatty acid oxidation. Point mutations in human VLCAD can produce an inborn error of metabolism called VLCAD deficiency that can lead to severe pathophysiologic consequences, including cardiomyopathy, hypoglycemia, and rhabdomyolysis. Discrete mutations in a structurally-uncharacterized C-terminal domain region of VLCAD cause enzymatic deficiency by an incompletely defined mechanism. Here, we conducted a structure-function study, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, computational modeling, and biochemical analyses, to characterize a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted α-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, our data support a structural basis for VLCAD deficiency in patients with discrete mutations in an α-helical membrane-binding motif, resulting in pathologic enzyme mislocalization.

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Topology, landscapes, and biomolecular energy transport

Cited by 8 publications

References 56 publications

Single-molecule diffusometry reveals no catalysis-induced diffusion enhancement of alkaline phosphatase as proposed by FCS experiments

Single-molecule diffusometry reveals no catalysis-induced diffusion enhancement of alkaline phosphatase as proposed by FCS experiments

Variation of Energy Transfer Rates across Protein–Water Contacts with Equilibrium Structural Fluctuations of a Homodimeric Hemoglobin

Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency

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