Mechanism of catalytic regulation by an allosteric hot spot in dihydrofolate reductase.

A distal allosteric hot spot in dihydrofolate reductase redistributes two globally similar conformations, where one is catalytically competent and the other is not.

• Why it matters: Distal perturbations can regulate catalysis, but the molecular pathway linking an allosteric site to chemical activity is still unclear.
• What they did: The study combined enhanced conformational sampling, reactive free-energy calculations of the chemical step, nonequilibrium molecular dynamics, evolutionary analysis, and experimental kinetics.
• The result: Nonequilibrium relaxation showed the mutant’s interconversion proceeds via stepwise local rearrangements, and a compensatory second-site mutation partially restores activity.

AI summary of the abstract · may contain errors · not medical advice · read the paper.