title: Random-walk enzymes.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.|Center for Applied Mathematical Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Chi H
authors.initials: CH
authors.lastname: Mak
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Phuong
authors.initials: P
authors.lastname: Pham
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Samir A
authors.initials: SA
authors.lastname: Afif
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.|Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Myron F
authors.initials: MF
authors.lastname: Goodman
mesh_terms: D002384:Catalysis; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004058:Diffusion; D004798:Enzymes / Q000737:chemistry / Q000235:genetics; D007700:Kinetics; D008958:Models, Molecular; D009010:Monte Carlo Method; D009154:Mutation; D013269:Stochastic Processes
chemical_list: D004798:Enzymes; D004247:DNA