The hydration structure of methylthiolate from QM/MM molecular dynamics

Area of Science:

• Biochemistry
• Computational Chemistry
• Molecular Dynamics

Background:

• Thiols, particularly cysteine residues, are crucial in biological systems.
• Deprotonated thiolates exhibit diverse enzymatic and chemical modification roles.
• Validated molecular mechanical force field parameters for thiolates are lacking due to scarce solvation data.

Purpose of the Study:

• To assess and validate CHARMM36 and Amber force field models for thiolates in aqueous solutions.
• To provide accurate structural and energetic data for thiolate solvation.
• To guide the development of improved molecular mechanical force fields for biomolecular simulations.

Main Methods:

• Free energy perturbation simulations.
• Hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations.
• Symmetry Adapted Perturbation Theory (SAPT) analysis.

Main Results:

• QM/MM MD simulations revealed methylthiolate hydration structure with S-water distances ~2 Å and coordination number ~6.
• CHARMM36 parameters accurately predicted thiolate S radius and hydration Gibbs energy.
• Amber force field's cysteine thiolate model showed inaccuracies in radius and hydration energy prediction.

Conclusions:

• Distinct non-bonded parameters are essential for protonated and deprotonated amino acid side chains in force fields.
• The CHARMM36 model demonstrates good performance for thiolate solvation.
• Accurate force field parameterization is critical for reliable biomolecular simulations involving thiolates.