The large size of most enzymes necessitates hybrid quantum mechanical-molecular mechanical (QM/MM) simulation for mechanism elucidation. Numerous convergence studies of QM/MM methods have revealed over the past several years that key energetic and structural properties approach asymptotic limits with only very large (ca. 500-1000 atom) QM regions. This slow convergence has been observed to be due in part to significant charge transfer between the core active site and surrounding protein environment, which cannot be addressed by improvement of MM force fields or the embedding method employed within QM/MM. I will discuss our recent development of systematic methodologies that enable atom-economical determination of optimal QM regions (typically ca. 200-300 atoms) and provide insight into the crucial interactions in enzyme active sites captured only in large QM regions. The two approaches, based on measuring the change in chemical environment around an active site or the degree of charge transfer between core substrates and the surrounding environment, produce robust, consistent, and readily validated results on test case enzymes (e.g., catechol O-methyltransferase, cytochrome P450cam, and hen eggwhite lysozyme) that asymptotically approach results from very large QM regions. These systematically selected QM regions enable identification of charge-transfer-mediated prolonged electrostatic attraction as a previously overlooked component of enzyme rate enhancement in group transfer across a wide family of methyltransferases. I will present how pairing our efforts with graphics-processing-unit-accelerated QM/MM simulation has enabled collection of over a nanosecond of enhanced sampling dynamics with range-separated hybrid density functional theory to reveal the magnitude of charge transfer and free energy barriers in QM/MM with QM regions up to 600 atoms in size. These simulations reveal dramatic fluctuations in the charge density mediated through hydrogen bonding interactions in the greater protein environment as a key component of enzyme action that is apparent only with large, systematically selected QM regions.

Uncovering the quantum mechanical origins of enzymatic catalysis with systematic QM/MM methods and accelerated, large-scale electronic structure

255th National Meeting (2018)

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