Evaluating the Functional Importance of Conformer-Dependent Atomic Partial Charge Assignment.

Area of Science:

• Computational chemistry
• Drug discovery
• Molecular modeling

Background:

• Physics-based methods, like binding free energy calculations, are vital for early-stage drug discovery.
• The accuracy of these methods hinges on precise ligand and protein preparation, including partial atomic charge assignment.
• Conformational dependence of partial charges is known, but its impact on free energy estimates is under-explored.

Purpose of the Study:

• To systematically investigate the downstream effects of variations in partial atomic charge generation on free energy calculations.
• To quantify the impact of different input conformers, charge assignment engines, and hardware on calculated absolute hydration free energies (AHFE).
• To highlight the importance of careful partial charge assignment for reproducible and accurate free energy predictions in drug discovery.

Main Methods:

• Utilized absolute hydration free energy calculations on smaller systems to minimize confounding factors.
• Varied input conformers, partial charge engines, and hardware during the charge generation process.
• Analyzed discrepancies in atomic partial charges and their subsequent impact on calculated AHFE values.

Main Results:

• Differences in input conformers for partial charge generation led to atomic charge discrepancies up to 0.681 e.
• These charge variations resulted in notable differences in calculated absolute hydration free energies.
• Even minor variations in partial charge assignment can significantly affect AHFE outcomes.

Conclusions:

• Partial atomic charge assignment is a critical step in free energy calculations, with conformational dependence significantly impacting results.
• Careful consideration and standardization of partial charge generation are necessary to ensure the accuracy and reproducibility of computational drug discovery.
• The observed effects are expected to be amplified in more complex protein-ligand binding free energy calculations.