Structure and Dynamics of the Isozymes II and IX of Human Carbonic Anhydrase.
Journal
ACS omega
ISSN: 2470-1343
Titre abrégé: ACS Omega
Pays: United States
ID NLM: 101691658
Informations de publication
Date de publication:
06 Sep 2022
06 Sep 2022
Historique:
received:
30
05
2022
accepted:
15
08
2022
entrez:
12
9
2022
pubmed:
13
9
2022
medline:
13
9
2022
Statut:
epublish
Résumé
Human carbonic anhydrases (HCAs) are responsible for the pH control and sensing in our body and constitute key components in the central pH paradigm connected to cancer therapeutics. However, little or no molecular level studies are available on the pH-dependent stability and functional dynamics of the known isozymes of HCA. The main objective of this Article is to report the first bench-marking study on the structure and dynamics of the two most efficient isozymes, HCA II and IX, at neutral pH using classical molecular dynamics (MD) and constant pH MD (CpHMD) simulations combined with umbrella sampling, transition path sampling, and Markov state models. Starting from the known crystal structures of HCA II and the monomeric catalytic domain of HCA IX (labeled as HCA IX-c), we have generated classical MD and CpHMD trajectories (of length 1 μs each). In all cases, the overall stability, RMSD, and secondary structure segments of the two isozymes are found to be quite similar. Functionally important dynamics of these two enzymes have been probed in terms of active site hydration, coordination of the Zn(II) ion to a transient excess water, and the formation of putative proton transfer paths. The most important difference between the two isozymes is observed for the side-chain fluctuations of His-64 that is expected to shuttle an excess proton out of the active site as a part of the rate-determining intramolecular proton transfer reaction. The relative stability of the stable inward and outward conformations of the His-64 side-chain and the underlying free energy surfaces are found to depend strongly on the isozyme. In each case, a lower free energy barrier is detected between predominantly inward conformations from predominantly outward ones when simulated under constant pH conditions. The kinetic rate constants of interconversion between different free energy basins are found to span 10
Identifiants
pubmed: 36092600
doi: 10.1021/acsomega.2c03356
pmc: PMC9453958
doi:
Types de publication
Journal Article
Langues
eng
Pagination
31149-31166Informations de copyright
© 2022 The Authors. Published by American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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