Dataset Information

Using Protein-Confined Proximity To Determine Chemical Reactivity.

ABSTRACT: Chemical reactivity is essential for functional modification of biomolecules with small molecules and the development of covalent drugs. The reactivity between a chemical functional group of a small molecule and that of a large biomolecule cannot be reliably predicted from the reactivity of the corresponding functional groups separately installed on two small molecules, because the proximity effect on reactivity resulting from the binding of the small molecule to the biomolecule is challenging to achieve by mixing two small molecules. Here we present a new strategy to determine the chemical reactivity of two functional groups in the context of close proximity afforded by proteins. The functional groups to be tested were separately installed at the interface of two interacting proteins in the format of amino acid side chains via the expansion of the genetic code. Reaction of the two functional groups resulted in covalent cross-linking of interacting proteins, readily detectable by gel electrophoresis. Using this strategy, we evolved new synthetases to genetically encode N?-fluoroacetyllysine (FAcK), an isosteric fluorine analogue of acetyllysine. We demonstrated that fluoroacetamide installed on FAcK, previously thought inert to biological functional groups, actually reacted with the thiol group of cysteine when in proximity. This strategy should be valuable for accurately evaluating chemical reactivity of small molecules toward large biomolecules, which will help avoid undesired side reactions of drugs and expand the repertoire of functional groups to covalently target biomolecules.

SUBMITTER: Kobayashi T

PROVIDER: S-EPMC5310709 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Using Protein-Confined Proximity To Determine Chemical Reactivity.

Kobayashi Tomonori T Hoppmann Christian C Yang Bing B Wang Lei L

Journal of the American Chemical Society 20161104 45

Chemical reactivity is essential for functional modification of biomolecules with small molecules and the development of covalent drugs. The reactivity between a chemical functional group of a small molecule and that of a large biomolecule cannot be reliably predicted from the reactivity of the corresponding functional groups separately installed on two small molecules, because the proximity effect on reactivity resulting from the binding of the small molecule to the biomolecule is challenging t ...[more]

PMID: 27797495

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Project description:Most wearable devices that measure movement in workplaces cannot determine the context in which people spend time. This study examined the accuracy of Bluetooth sensing (10-second intervals) via the ActiGraph GT9X Link monitor to determine location in an office setting, using two simple, bespoke algorithms.For one work day (mean±SD 6.2±1.1 hours), 30 office workers (30% men, aged 38±11 years) simultaneously wore chest-mounted cameras (video recording) and Bluetooth-enabled monitors (initialised as receivers) on the wrist and thigh. Additional monitors (initialised as beacons) were placed in the entry, kitchen, photocopy room, corridors, and the wearer's office. Firstly, participant presence/absence at each location was predicted from the presence/absence of signals at that location (ignoring all other signals). Secondly, using the information gathered at multiple locations simultaneously, a simple heuristic model was used to predict at which location the participant was present. The Bluetooth-determined location for each algorithm was tested against the camera in terms of F-scores.When considering locations individually, the accuracy obtained was excellent in the office (F-score = 0.98 and 0.97 for thigh and wrist positions) but poor in other locations (F-score = 0.04 to 0.36), stemming primarily from a high false positive rate. The multi-location algorithm exhibited high accuracy for the office location (F-score = 0.97 for both wear positions). It also improved the F-scores obtained in the remaining locations, but not always to levels indicating good accuracy (e.g., F-score for photocopy room ?0.1 in both wear positions).The Bluetooth signalling function shows promise for determining where workers spend most of their time (i.e., their office). Placing beacons in multiple locations and using a rule-based decision model improved classification accuracy; however, for workplace locations visited infrequently or with considerable movement, accuracy was below desirable levels. Further development of algorithms is warranted.

Dataset Information

Using Protein-Confined Proximity To Determine Chemical Reactivity.

Publications

Using Protein-Confined Proximity To Determine Chemical Reactivity.

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