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Single molecule force spectroscopy and computation are used to evaluate substituent effects on the disrotatory ring opening reaction of cyclobutene to butadiene, accessedviacovalent polymer mechanochemistry. 

The mechanisms that underly the adaptation of enzyme activities and stabilities to temperature are fundamental to our understanding of molecular evolution and how enzymes work. Here, we investigate the molecular and evolutionary mechanisms of enzyme temperature adaption, combining deep mechanistic studies with comprehensive sequence analyses of thousands of enzymes. We show that temperature adaptation in ketosteroid isomerase (KSI) arises primarily from one residue change with limited, local epistasis, and we establish the underlying physical mechanisms. This residue change occurs in diverse KSI backgrounds, suggesting parallel adaptation to temperature. We identify residues associated with organismal growth temperature across 1005 diverse bacterial enzyme families, suggesting widespread parallel adaptation to temperature. We assess the residue properties, molecular interactions, and interaction networks that appear to underly temperature adaptation. 

Dynamic effects are an important determinant of chemical reactivity and selectivity, but the deliberate manipulation of atomic motions during a chemical transformation is not straightforward. Here, we demonstrate that extrinsic force exerted upon cyclobutanes by stretching pendant polymer chains influences product selectivity through force-imparted nonstatistical dynamic effects on the stepwise ring-opening reaction. The high product stereoselectivity is quantified by carbon-13 labeling and shown to depend on external force, reactant stereochemistry, and intermediate stability. Computational modeling and simulations show that, besides altering energy barriers, the mechanical force activates reactive intramolecular motions nonstatistically, setting up “flyby trajectories” that advance directly to product without isomerization excursions. A mechanistic model incorporating nonstatistical dynamic effects accounts for isomer-dependent mechanochemical stereoselectivity.