Transition-State Vibrational Analysis and Isotope Effects for COMT-Catalyzed Methyl Transfer

Area of Science:

• Computational Chemistry
• Enzyme Catalysis
• Biophysical Chemistry

Background:

• Catechol O-methyltransferase (COMT) catalyzes methyl transfer reactions.
• Isotopic partition-function ratios (IPFRs) are crucial for understanding reaction mechanisms and isotopic effects.
• Hybrid quantum mechanics/molecular mechanics (QM/MM) methods are employed to model complex enzymatic systems.

Purpose of the Study:

• To analyze IPFRs for transition structures (TSs) in COMT-catalyzed methyl transfer.
• To critically assess the ability of smaller computational models (Hessians) to reproduce IPFR trends.
• To investigate the influence of ponderal effects and protein residues on IPFRs.

Main Methods:

• Computation of IPFRs for TSs using hybrid QM/MM methods.
• Analysis of smaller extracted Hessians against larger QM/MM Hessians for IPFR accuracy.
• Calculation of harmonic frequencies, mean-square amplitudes, and potential energy scans to assess anharmonicity.
• Investigation of ponderal effects by varying system mass.

Main Results:

• A 6-atom Hessian accurately reproduced alpha-tritium (α-T3) IPFRs but not alpha-carbon-14 (α-14C) IPFRs.
• Ponderal effects show α-14C IPFRs tend toward a minimum and α-T3 IPFRs toward a maximum with increasing system mass.
• The transition vector is primarily composed of motions within the methyl donor and acceptor, with minimal contribution from protein residues.
• Valence force constants differ significantly from previous estimates, challenging the compression hypothesis.

Conclusions:

• Smaller computational models are insufficient for accurately predicting all isotopic effects in COMT catalysis.
• Ponderal effects play a significant role in determining IPFRs, particularly for heavier isotopes.
• The catalytic mechanism does not appear to be strongly influenced by protein residue interactions or compression effects.