Convergent Protocols for Computing Protein-Ligand Interaction Energies Using Fragment-Based Quantum Chemistry.

Area of Science:

• Computational Chemistry
• Biomolecular Modeling
• Quantum Chemistry

Background:

• Electronic structure calculations face computational challenges with large molecular systems.
• Fragment-based methods offer a scalable alternative for high-level quantum chemistry.

Purpose of the Study:

• To compute protein-ligand interaction energies in large systems using fragmentation.
• To develop and utilize a new software platform for fragment-based calculations.

Main Methods:

• Employing a screened many-body expansion within a fragmentation framework.
• Utilizing a minimal-basis semiempirical method (HF-3c) for convergence tests.
• Comparing results with conventional supramolecular electronic structure calculations and density functional theory (DFT).

Main Results:

• Two-body fragmentation calculations accurately reproduced interaction energies (within 1 kcal/mol) at approximately 1% of the computational cost.
• HF-3c trends were found to be illustrative of DFT results with high-quality basis sets.
• The fragmentation approach enables high-accuracy quantum chemistry for systems of unprecedented size.

Conclusions:

• Fragment-based quantum chemistry, implemented with a screened many-body expansion, provides a computationally efficient and accurate method for large biomolecular systems.
• This approach facilitates the generation of high-quality training data for machine learning applications in computational chemistry.