Improved Description of Sulfur Charge Anisotropy in OPLS Force Fields: Model Development and Parameterization

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Force Field Development

Background:

• Standard atomic point-charge models in molecular mechanics struggle to represent electronic anisotropy crucial for directional noncovalent interactions.
• Sulfur's lone pairs and σ-holes contribute to various directional interactions, necessitating improved modeling.
• Existing force fields lack sufficient charge anisotropy representation for sulfur-containing systems.

Purpose of the Study:

• To develop and validate a new atomic point-charge model for sulfur compounds to address charge anisotropy.
• To enhance the accuracy of molecular mechanics force fields (OPLS-AA and OPLS/CM5) for sulfur interactions.
• To improve the prediction of hydration free energies, noncovalent energetics, and conformational preferences.

Main Methods:

• Introduction of off-atom charged sites into the OPLS-AA and OPLS/CM5 force fields for sulfur compounds.
• Parameter optimization using liquid-state properties, quantum mechanical calculations (torsional and noncovalent energetics), and electrostatic potentials.
• Validation through molecular dynamic simulations of blocked dipeptides containing cysteine and methionine.

Main Results:

• Significant reduction in mean unsigned errors for computed free energies of hydration (from ~1.4 to 0.4-0.7 kcal/mol).
• Enhanced accuracy in the directionality and energetics of molecular complexes involving sulfur-containing hydrogen and halogen bonds.
• Accurate reproduction of unusual conformational preferences due to 1,4-intramolecular chalcogen bonds in sulfur compounds.

Conclusions:

• The novel model effectively addresses electronic anisotropy in sulfur compounds using off-atom charge sites.
• The developed force field parameters show good transferability to biologically relevant amino acids like cysteine and methionine.
• The study provides a robust methodology for parameterizing other systems requiring improved charge anisotropy representation.