Back to Search
Start Over
Allosteric regulatory control in dihydrofolate reductase is revealed by dynamic asymmetry.
- Source :
-
Protein science : a publication of the Protein Society [Protein Sci] 2023 Aug; Vol. 32 (8), pp. e4700. - Publication Year :
- 2023
-
Abstract
- We investigated the relationship between mutations and dynamics in Escherichia coli dihydrofolate reductase (DHFR) using computational methods. Our study focused on the M20 and FG loops, which are known to be functionally important and affected by mutations distal to the loops. We used molecular dynamics simulations and developed position-specific metrics, including the dynamic flexibility index (DFI) and dynamic coupling index (DCI), to analyze the dynamics of wild-type DHFR and compared our results with existing deep mutational scanning data. Our analysis showed a statistically significant association between DFI and mutational tolerance of the DHFR positions, indicating that DFI can predict functionally beneficial or detrimental substitutions. We also applied an asymmetric version of our DCI metric (DCI <subscript>asym</subscript> ) to DHFR and found that certain distal residues control the dynamics of the M20 and FG loops, whereas others are controlled by them. Residues that are suggested to control the M20 and FG loops by our DCI <subscript>asym</subscript> metric are evolutionarily nonconserved; mutations at these sites can enhance enzyme activity. On the other hand, residues controlled by the loops are mostly deleterious to function when mutated and are also evolutionary conserved. Our results suggest that dynamics-based metrics can identify residues that explain the relationship between mutation and protein function or can be targeted to rationally engineer enzymes with enhanced activity.<br /> (© 2023 The Protein Society.)
Details
- Language :
- English
- ISSN :
- 1469-896X
- Volume :
- 32
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Protein science : a publication of the Protein Society
- Publication Type :
- Academic Journal
- Accession number :
- 37313628
- Full Text :
- https://doi.org/10.1002/pro.4700