Allosteric communication in Dihydrofolate Reductase: Signaling network and pathways for closed to occluded transition and back

TL;DR

This study investigates the allosteric signaling pathways in E. coli DHFR, revealing how conformational changes between closed and occluded states are transmitted through specific residue networks and involve loop motions.

Contribution

It combines sequence-based analysis and polymer modeling to identify allosteric residue networks and elucidate the kinetics of conformational transitions in DHFR.

Findings

Residue network identified as allosteric wiring diagram

Met20 loop exhibits sliding motion during transitions

Residues facilitating loop motion are part of allosteric pathways

Abstract

E. Coli. dihydrofolate reductase (DHFR) undergoes conformational transitions between the closed (CS) and occluded (OS) states which, respectively, describe whether the active site is closed or occluded by the Met20 loop. A sequence-based approach is used to identify a network of residues that represents the allostery wiring diagram. We also use a self-organized polymer model to monitor the kinetics of the CS->OS and the reverse transitions. a sliding motion of Met20 loop is observed. The residues that facilitate the Met20 loop motion are part of the network of residues that transmit allosteric signals during the CS->OS transition.