Allosteric regulatory control in dihydrofolate reductase is revealed by dynamic asymmetry
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 dyn...
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Published in | Protein science Vol. 32; no. 8; pp. e4700 - n/a |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Hoboken, USA
John Wiley & Sons, Inc
01.08.2023
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
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Summary: | 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 (DCIasym) 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 DCIasym 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Review Editor: Nir Ben‐Tal. |
ISSN: | 0961-8368 1469-896X 1469-896X |
DOI: | 10.1002/pro.4700 |