Toward Functional Type III [Fe]‐Hydrogenase Biomimics for H2 Activation: Insights from Computation

The chemistry of [Fe]‐hydrogenase has attracted significant interest due to its ability to activate molecular hydrogen. The intriguing properties of this enzyme have prompted the synthesis of numerous small molecule mimics aimed at activating H₂. Despite considerable effort, a majority of these compounds remain nonfunctional for hydrogenation reactions. By using a recently synthesized model as an entry point, seven biomimetic complexes have been examined through DFT computations to probe the influence of ligand environment on the ability of a mimic to bind and split H₂. One mimic, featuring a bidentate diphosphine group incorporating an internal nitrogen base, was found to have particularly attractive energetics, prompting a study of the role played by the proton/hydride acceptor necessary to complete the catalytic cycle. Computations revealed an experimentally accessible energetic pathway involving a benzaldehyde proton/hydride acceptor and the most promising catalyst.     

The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger FEP

In drug discovery, protonation states and tautomerization are easily overlooked. Through a Merck–Rutgers collaboration, this paper re-examined the initial settings and preparations for the Thermodynamic Integration (TI) calculation in AMBER Free-Energy Workflows, demonstrating the value of careful consideration of ligand protonation and tautomer state. Finally, promising results comparing AMBER TI and Schrödinger FEP+ are shown that should encourage others to explore the value of TI in routine Structure-based Drug Design.