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2015 ; 92
(3
): 032717
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Random-walk enzymes
#MMPMID26465508
Mak CH
; Pham P
; Afif SA
; Goodman MF
Phys Rev E Stat Nonlin Soft Matter Phys
2015[Sep]; 92
(3
): 032717
PMID26465508
show ga
Enzymes that rely on random walk to search for substrate targets in a
heterogeneously dispersed medium can leave behind complex spatial profiles of
their catalyzed conversions. The catalytic signatures of these random-walk
enzymes are the result of two coupled stochastic processes: scanning and
catalysis. Here we develop analytical models to understand the conversion
profiles produced by these enzymes, comparing an intrusive model, in which
scanning and catalysis are tightly coupled, against a loosely coupled passive
model. Diagrammatic theory and path-integral solutions of these models revealed
clearly distinct predictions. Comparison to experimental data from catalyzed
deaminations deposited on single-stranded DNA by the enzyme activation-induced
deoxycytidine deaminase (AID) demonstrates that catalysis and diffusion are
strongly intertwined, where the chemical conversions give rise to new stochastic
trajectories that were absent if the substrate DNA was homogeneous. The C?U
deamination profiles in both analytical predictions and experiments exhibit a
strong contextual dependence, where the conversion rate of each target site is
strongly contingent on the identities of other surrounding targets, with the
intrusive model showing an excellent fit to the data. These methods can be
applied to deduce sequence-dependent catalytic signatures of other DNA
modification enzymes, with potential applications to cancer, gene regulation, and
epigenetics.
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