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Experimental assessment of the reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates, and sensitivity of cofactors such as iron sulfur clusters. Here we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical SAM enzyme CPH4 synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg2+, Ca2+ or Na+. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semi-empirical methods. The impact of intermolecular interactions on RSE was clearly established and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates, as candidates for catalytic turnover by QueE.