Multidimensional Free Energy and Accelerated Quantum Library Methods Provide a Gateway to Glycoenzyme Conformational,...

Area of Science:

• Computational Chemistry and Chemical Biology
• Enzyme Catalysis and Reaction Dynamics
• Molecular Modeling and Simulation

Background:

• Simulating enzyme reactions, particularly those involving glycoenzymes, is computationally challenging due to complex protein and substrate dynamics.
• Accurate simulation requires rigorous sampling of protein and carbohydrate conformations and unbiased treatment of electron dynamics.

Purpose of the Study:

• To demonstrate the effectiveness of novel computational methods, FEARCF and QSL, for simulating complex enzyme reaction landscapes.
• To elucidate the catalytic mechanism of the glycoenzyme β-N-acetylglucosamine transferase (OGT) using these advanced simulation techniques.

Main Methods:

• Developed FEARCF (flat histogram free energy method) for multidimensional sampling and phase space coverage.
• Developed QSL (Quantum Supercharger Library) to accelerate ab initio electronic wave function computations on GPUs.
• Combined FEARCF and QSL for ab initio QM/MM reaction dynamics simulations, coupled with legacy codes like GAMESS and NWCHEM.

Main Results:

• The combined FEARCF and QSL methods enabled feasible simulation of enzyme catalysis, specifically for carbohydrate-processing enzymes.
• Simulations revealed OGT's role in distorting the β-N-acetylglucosamine substrate's pyranose ring towards the transition state conformation.
• OGT was found to lower the reaction pathway and stabilize the transition state E3 ring conformer by 1.63 kcal/mol.

Conclusions:

• The pairing of QSL-accelerated QM/MM dynamics with FEARCF multidimensional sampling effectively explores the interplay between reaction and conformational space in enzyme catalysis.
• This computational approach allows for the discovery of molecular and electronic mechanisms in enzyme catalysis that are difficult to access experimentally.
• The study successfully models the dynamics of complex carbohydrate-catalyzed reactions, providing deep insights into enzymatic mechanisms.