Journal article
DNA polymerase conformational dynamics and the role of fidelity-conferring residues: Insights from computational simulations
- Abstract:
- Herein we investigate the molecular bases of DNA polymerase I conformational dynamics that underlie the replication fidelity of the enzyme. Such fidelity is determined by conformational changes that promote the rejection of incorrect nucleotides before the chemical ligation step. We report a comprehensive atomic resolution study of wild type and mutant enzymes in different bound states and starting from different crystal structures, using extensive molecular dynamics (MD) simulations that cover a total timespan of ~5 ms. The resulting trajectories are examined via a combination of novel methods of internal dynamics and energetics analysis, aimed to reveal the principal molecular determinants for the (de)stabilization of a certain conformational state. Our results show that the presence of fidelity-decreasing mutations or the binding of incorrect nucleotides in ternary complexes tend to favor transitions from closed toward open structures, passing through an ensemble of semi-closed intermediates. The latter ensemble includes the experimentally observed ajar conformation which, consistent with previous experimental observations, emerges as a molecular checkpoint for the selection of the correct nucleotide to incorporate. We discuss the implications of our results for the understanding of the relationships between the structure, dynamics, and function of DNA polymerase I at the atomistic level.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 3.1MB, Terms of use)
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- Publisher copy:
- 10.3389/fmolb.2016.00020
Authors
- Publisher:
- Frontiers Media
- Journal:
- Frontiers in Molecular Biosciences More from this journal
- Volume:
- 3
- Issue:
- MAY
- Article number:
- 20
- Publication date:
- 2016-05-27
- Acceptance date:
- 2016-05-10
- DOI:
- EISSN:
-
2296-889X
- Pmid:
-
27303671
- Language:
-
English
- Keywords:
- Pubs id:
-
pubs:628301
- UUID:
-
uuid:3fb6a57f-fb1e-41a0-9c2b-4facc621c9df
- Local pid:
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pubs:628301
- Source identifiers:
-
628301
- Deposit date:
-
2019-02-07
Terms of use
- Copyright holder:
- Meli et al
- Copyright date:
- 2016
- Notes:
- Copyright © 2016 Meli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Licence:
- CC Attribution (CC BY)
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