Adapted DFTB3 Repulsive Potentials Reach DFT Accuracy for Hydride Transfer Reactions in Enzymes.

Area of Science:

• Biochemistry
• Computational Chemistry
• Enzymology

Background:

• Enzymatic hydride transfer reactions are vital in metabolism but computationally challenging to model accurately.
• Current methods like DFT QM/MM offer accuracy but are computationally expensive, limiting large-scale simulations.
• Semi-empirical methods like DFTB3 provide efficiency but lack accuracy for these reactions.

Purpose of the Study:

• To improve the accuracy of the DFTB3 method for modeling enzymatic hydride transfer reactions.
• To develop a systematic approach for optimizing DFTB3's description of the reaction potential energy surface.
• To enable more efficient and accurate computational simulations of enzyme mechanisms.

Main Methods:

• Modified DFTB3 repulsive potential functions using linear combinations of harmonic functions.
• Guided optimization based on C-H and C-C distance distributions along the reaction path.
• Validated the adapted DFTB3 Hamiltonian on Crotonyl-CoA Carboxylase/Reductase (Ccr), a 1,4-dihydropyridine reaction, and Dihydrofolate Reductase (DHFR).

Main Results:

• The optimized DFTB3 Hamiltonian accurately reproduced the reference DFT activation barrier for Ccr (within 0.1 kcal/mol).
• The adapted method successfully predicted activation barriers for other hydride transfer reactions (1,4-dihydropyridine and DHFR), matching DFT and experimental data.
• Achieved significant improvement in describing the potential energy surface for hydride transfer.

Conclusions:

• The developed DFTB3 modification offers a computationally efficient and accurate approach for modeling enzymatic hydride transfer reactions.
• This method facilitates more extensive molecular dynamics simulations, aiding enzyme engineering and drug discovery.
• The transferability of the optimized Hamiltonian across different enzyme systems demonstrates its broad applicability.