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arXiv · 2607.09769

Challenges in the simulation of enzymatic transition states with emerging multireference character

Valentin Kasper·Sanjoy Ray·Matthias Kaiser
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Abstract

Highly successful drugs, such as transition-state inhibitors, were designed by mimicking the precise geometry of enzymatic transition states, a strategy that requires quantum chemistry accurate enough to specify molecular structure at sub-\AA\ resolution. A central challenge during such a quantum chemistry simulation is that classical single-reference method can deviate substantially from the exact energy at strongly correlated transition states. We study the breakdown due to multireference character by studying a model system with a multireference transition state. In this work we present a proprietary PexMachina solver which reproduces the exact ground-state energy throughout the transition state scan, while single-reference methods struggle for certain geometries to achieve chemical accuracy.

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Valentin Kasper, Sanjoy Ray, Matthias Kaiser. 2026-07-07. Challenges in the simulation of enzymatic transition states with emerging multireference character. https://arxiv.org/abs/2607.09769

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