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Computer simulations explain mutation-induced effects on the DNA editing by adenine base editors.

ABSTRACT: Adenine base editors, which were developed by engineering a transfer RNA adenosine deaminase enzyme (TadA) into a DNA editing enzyme (TadA*), enable precise modification of A:T to G?C base pairs. Here, we use molecular dynamics simulations to uncover the structural and functional roles played by the initial mutations in the onset of the DNA editing activity by TadA*. Atomistic insights reveal that early mutations lead to intricate conformational changes in the structure of TadA*. In particular, the first mutation, Asp108Asn, induces an enhancement in the binding affinity of TadA to DNA. In silico and in vivo reversion analyses verify the importance of this single mutation in imparting functional promiscuity to TadA* and demonstrate that TadA* performs DNA base editing as a monomer rather than a dimer.

SUBMITTER: Rallapalli KL

PROVIDER: S-EPMC7056309 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Computer simulations explain mutation-induced effects on the DNA editing by adenine base editors.

Rallapalli Kartik L KL Komor Alexis C AC Paesani Francesco F

Science advances 20200304 10

Adenine base editors, which were developed by engineering a transfer RNA adenosine deaminase enzyme (TadA) into a DNA editing enzyme (TadA*), enable precise modification of A:T to G⋮C base pairs. Here, we use molecular dynamics simulations to uncover the structural and functional roles played by the initial mutations in the onset of the DNA editing activity by TadA*. Atomistic insights reveal that early mutations lead to intricate conformational changes in the structure of TadA*. In particular, ...[more]

PMID: 32181363

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