2021
DOI: 10.1101/2021.08.13.456233
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Estimation of effective concentrations enforced by complex linker architectures from conformational ensembles

Abstract: Proteins and protein assemblies often tether interaction partners to strengthen interactions, to regulate activity through auto-inhibition or -activation, or to boost enzyme catalysis. Tethered reactions are regulated by the architecture of tether, which define an effective concentration of the interactors. Effective concentrations can be estimated theoretically for simple linkers via polymer models, but there is currently no general method for estimating effective concentrations for complex linker architectur… Show more

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Cited by 3 publications
(5 citation statements)
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“…The effective concentration was determined from an ensemble of 10.000 conforms where MBD2:p66α is simulated as a rigid rod, and disordered segments are treated as a random chain (Fig S3). 25 For the 120-residue GS-linker this resulted in a calculated C eff of 388 μM. The numerical simulations predict that steady-state phosphorylation rates have a bell-shaped dependence on the docking strength ( k off ) for substrate concentrations from 0.1 to 100 μM (Fig.…”
Section: Resultsmentioning
confidence: 93%
See 2 more Smart Citations
“…The effective concentration was determined from an ensemble of 10.000 conforms where MBD2:p66α is simulated as a rigid rod, and disordered segments are treated as a random chain (Fig S3). 25 For the 120-residue GS-linker this resulted in a calculated C eff of 388 μM. The numerical simulations predict that steady-state phosphorylation rates have a bell-shaped dependence on the docking strength ( k off ) for substrate concentrations from 0.1 to 100 μM (Fig.…”
Section: Resultsmentioning
confidence: 93%
“…To calculate C eff covering this complexity, a newly developed approach based on conformational ensembles was used. 25 Briefly, a physically realistic ensemble of the linker was modelled using the “Ensemble Optimization Method” (EOM). As EOM cannot handle heterodimers, the p66a-MBD2 coiled-coil was replaced with a α-helical poly-alanine rod, which has a similar length and produces the same end-to-end distribution as the folded domain.…”
Section: Methodsmentioning
confidence: 99%
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“…Besides orienting the PAD domain at the right distance to bind a double stranded DNA as shown by previous crystallographic studies 14,60,61 , another intriguing possibility is the effective concentration of this domain. It could be shown previously for unrelated enzymes, kinases that facilitate phosphorylation of their substrates, that in cases when the enzyme is tethered to the substrate these linker regions have a direct influence on the catalytic rate 62,63 . In agreement with this general interpretation of the importance of the linker region already previous work on chimeric archaeal DinB homologous protein with varying linker sequences high-lighted the importance of this linker region for the catalytic efficiency of the enzyme 15,26 .…”
Section: Discussionmentioning
confidence: 99%
“…Kjaergaard 24 developed an ensemble approach to model the effect of complex linker architectures on bivalent avidity. This analysis confirmed the findings of Galimidi et al 22 that a rigid linker, tuned to the distance and flanked by short flexible segments, could give enhanced avidity relative to a fully flexible linker.…”
Section: T H Imentioning
confidence: 99%