PDB ligand conformational energies calculated quantum-mechanically.

Area of Science:

• Computational Chemistry
• Structural Biology
• Drug Discovery

Background:

• Accurate conformational energies of protein-ligand complexes are crucial for understanding molecular interactions and drug design.
• Previous studies provided foundational data, but advancements in computational methods and data availability necessitate updated analyses.
• The Protein Data Bank (PDB) offers a vast repository of experimental 3D structures, including numerous small-molecule ligands.

Purpose of the Study:

• To present an updated and improved analysis of conformational energies for protein-ligand complexes.
• To enhance the quality and selection of ligand instances and refine energy calculation methodologies.
• To investigate the relationship between conformational energies and various structural and crystallographic parameters.

Main Methods:

• A high-quality subset of ligand instances was curated from the Ligand Expo database within the PDB.
• Conformational energies were calculated using density functional theory (DFT) with B3LYP functional and 6-31G(d) basis set, followed by single-point energy calculations at B3LYP/6-311++G(3df,2p).
• Stepwise optimization of internal degrees of freedom was employed, and calculations were repeated with the IEF-PCM solvent model and molecular mechanics force fields.

Main Results:

• Significant conformational energy differences (0 to ~25 kcal/mol) were observed, generally independent of crystallographic resolution.
• Higher energy outliers were noted only at resolutions better than 1.3 Å.
• Conformational energies correlated with molecular size and flexibility but not with crystallographic quality metrics (e.g., DPI, R(free)) or ligand-specific metrics (e.g., OWAB, RSR, RSCC).

Conclusions:

• The study provides a robust dataset and analysis of protein-ligand conformational energies, improving upon previous work.
• The findings suggest that conformational energy is influenced by intrinsic molecular properties rather than solely by crystallographic data quality.
• The results contribute valuable insights for computational drug design and understanding ligand binding in biological systems.