The hydration structure of methylthiolate from QM/MM molecular dynamics

Thiols are widely present in biological systems, most notably as the side chain of cysteine amino acids in proteins. Thiols can be deprotonated to form a thiolate which affords a diverse range of enzymatic activity and modes for chemical modification of proteins. Parameters for modeling thiolates using molecular mechanical force fields have not yet been validated, in part due to the lack of structural data on thiolate solvation. Here, the CHARMM36 and Amber models for thiolates in aqueous solutions are assessed using free energy perturbation and hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. The hydration structure of methylthiolate was calculated from 1 ns of QM/MM MD (PBE0-D3/def2-TZVP//TIP3P), which shows that the water-S^- distances are approximately 2 Å with a coordination number near 6. The CHARMM thiolate parameters predict a thiolate S radius close to the QM/MM value and predict a hydration Gibbs energy of -329.2 kJ/mol, close to the experimental value of -318 kJ/mol. The cysteine thiolate model in the Amber force field underestimates the thiolate radius by 0.2 Å and overestimates the thiolate hydration energy by 119 kJ/mol because it uses the same Lennard-Jones parameters for thiolates as for thiols. A recent Drude polarizable model for methylthiolate with optimized thiolate parameters also performs well. SAPT2+ [Symmetry Adapted Perturbation Theory (SAPT)] analysis indicates that exchange repulsion is larger for the methylthiolate, consistent with it having a more diffuse electron density distribution in comparison with the parent thiol. These data demonstrate that it is important to define distinct non-bonded parameters for the protonated/deprotonated states of amino acid side chains in molecular mechanical force fields.