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 QM/MM MD simulations. The hydration structure of methylthiolate was calculated from 1 ns of QM/MM MD (PBE0/def2-TZVP//TIP3P), which show that the water–S- distances are approximately 2 Å. The CHARMM thiolate parameters predict a thiolate S radius close to the QM/MM value and predict a hydration Gibbs energy of -331 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+ analysis indicates exchange repulsion is larger for the methylthiolate, consistent with it having a more diffuse electron density distribution in comparison to 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.

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 QM/MM MD simulations. The hydration structure of methylthiolate was calculated from 1 ns of QM/MM MD (PBE0/def2-TZVP//TIP3P), which show that the water–S- distances are approximately 2 Å. The CHARMM thiolate parameters predict a thiolate S radius close to the QM/MM value and predict a hydration Gibbs energy of -331 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+ analysis indicates exchange repulsion is larger for the methylthiolate, consistent with it having a more diffuse electron density distribution in comparison to 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.

Evaluating Force-Field London Dispersion Coefficients Using the Exchange-Hole Dipole Moment Model

<p>The exchange-hole dipole moment (XDM) model from density-functional theory predicts atomic and molecular London dispersion coefficients from first principles, providing an innovative strategy to validate the dispersion terms of molecular-mechanical force fields. In this work, the XDM model was used to obtain the London dispersion coefficients of 88 organic molecules relevant to biochemistry and pharmaceutical chemistry and the values compared with those derived from the Lennard-Jones parameters of the CGenFF, GAFF, OPLS, and Drude polarizable force fields…..(see full abstract). Finally, XDM-derived dispersion coefficients were used to parameterize molecular-mechanical force fields for five liquids – benzene, toluene, cyclohexane, n-pentane, and n-hexane – which resulted in improved accuracy in the computed enthalpies of vaporization despite only having to evaluate a much smaller section of the parameter space.</p>

Evaluating Force-Field London Dispersion Coefficients Using the Exchange-Hole Dipole Moment Model

<p>The exchange-hole dipole moment (XDM) model from density-functional theory predicts atomic and molecular London dispersion coefficients from first principles, providing an innovative strategy to validate the dispersion terms of molecular-mechanical force fields. In this work, the XDM model was used to obtain the London dispersion coefficients of 88 organic molecules relevant to biochemistry and pharmaceutical chemistry and the values compared with those derived from the Lennard-Jones parameters of the CGenFF, GAFF, OPLS, and Drude polarizable force fields…..(see full abstract). Finally, XDM-derived dispersion coefficients were used to parameterize molecular-mechanical force fields for five liquids – benzene, toluene, cyclohexane, n-pentane, and n-hexane – which resulted in improved accuracy in the computed enthalpies of vaporization despite only having to evaluate a much smaller section of the parameter space.</p>