Journal article
Evolutionary Effects on Bound Substrate p K a in Dihydrofolate Reductase
Journal of the American Chemical Society, Vol.140(48), pp.16650-16660
12/05/2018
DOI: 10.1021/jacs.8b09089
PMID: 30398861
Abstract
In the present study, we address the effect of active site structure and dynamics of different dihydrofolate reductase (DHFR) isoforms on the p K
of the bound substrate 7,8-dihydrofolate, in an attempt to understand possible evolutionary trends. We apply a hybrid QM/MM free energy perturbation method to estimate the p K
of the N5 position of the bound substrate. We observe a gradual increase in N5 basicity as we move from primitive to more evolved DHFR isoforms. Structural analysis of these isoforms reveals a gradual sequestering of water molecules from the active site in the more evolved enzymes, thereby modulating the local dielectric environment near the substrate. Furthermore, the present study reveals a clear correlation between active site hydration and the N5 p K
of the substrate. We emphasize the role of the M20 loop in controlling the active site hydration level, via a preorganized active site with a more hydrophobic environment and reduced loop flexibility as evolution progresses from bacterial to the human enzyme.
Details
- Title: Subtitle
- Evolutionary Effects on Bound Substrate p K a in Dihydrofolate Reductase
- Creators
- Anil R Mhashal - Department of Chemistry , Bar-Ilan University , Ramat-Gan 5290002 , IsraelYaron Pshetitsky - Department of Chemistry , Bar-Ilan University , Ramat-Gan 5290002 , IsraelChristopher M Cheatum - Department of Chemistry , University of Iowa , Iowa City , Iowa 52242 , United StatesAmnon Kohen - Department of Chemistry , University of Iowa , Iowa City , Iowa 52242 , United StatesDan Thomas Major - Department of Chemistry , Bar-Ilan University , Ramat-Gan 5290002 , Israel
- Resource Type
- Journal article
- Publication Details
- Journal of the American Chemical Society, Vol.140(48), pp.16650-16660
- DOI
- 10.1021/jacs.8b09089
- PMID
- 30398861
- ISSN
- 0002-7863
- eISSN
- 1520-5126
- Grant note
- DOI: 10.13039/501100001742, name: United States-Israel Binational Science Foundation, award: 2012340; DOI: 10.13039/501100003977, name: Israel Science Foundation, award: 2146/15
- Language
- English
- Date published
- 12/05/2018
- Academic Unit
- Liberal Arts and Science Admin; Chemistry
- Record Identifier
- 9984216701202771
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