Evaluating the London Dispersion Coefficients of Protein Force Fields Using the Exchange-Hole Dipole Moment Model

Evan T. Walters; Mohamad Mohebifar; Erin R. Johnson; Christopher N. Rowley

doi:10.1021/acs.jpcb.8b02814

Evaluating the London Dispersion Coefficients of Protein Force Fields Using the Exchange-Hole Dipole Moment Model

10.26434/chemrxiv.6024410.v1 ◽

2018 ◽

Author(s):

Evan T. Walters ◽

Mohamad Mohebifar ◽

Erin R. Johnson ◽

Christopher Rowley

Keyword(s):

Dipole Moment ◽

Force Fields ◽

Higher Order ◽

Side Chain ◽

Dispersion Interactions ◽

Dispersion Coefficients ◽

Hydration Energies ◽

London Dispersion ◽

Higher Order Dispersion ◽

Order Dispersion

<div>London dispersion is one of the fundamental intermolecular interactions involved in protein folding and dynamics. The popular CHARMM36, Amber ff14sb, and OPLS-</div><div>AA force fields represent these interactions through the C6 /r 6 term of the Lennard-Jones potential. The C6 parameters are assigned empirically, so these parameters are</div><div>not necessarily a realistic representation of the true dispersion interactions. In this work, dispersion coefficients of all three force fields were compared to corresponding</div><div>values from quantum-chemical calculations using the exchange-hole dipole moment (XDM) model. The force field values were found to be roughly 50% larger than the XDM values for protein backbone and side-chain models. The CHARMM36 and Amber OL15 force fields for nucleic acids were also found to exhibit this trend. To explore how these elevated dispersion coefficients affect predicted properties, the hydration energies of the side-chain models were calculated using the staged REMD-TI method of Deng and Roux for the CHARMM36, Amber ff14sb, and OPLS-AA force fields. Despite having large C 6 dispersion coefficients, these force fields predict side-chain hydration energies that are in generally good agreement with the experimental values, including for hydrocarbon residues where the dispersion component is the dominant attractive solute–solvent interaction. This suggests that these force fields predict the correct total strength of dispersion interactions, despite C6 coefficients that are considerably larger than XDM predicts. An analytical expression for the water–methane dispersion energy using XDM dispersion coefficients shows that that higher-order dispersion terms(i.e., C 8 and C 10 ) account for roughly 37.5% of the hydration energy of methane. This suggests that the C 6 dispersion coefficients used in contemporary force fields are</div><div>elevated to account for the neglected higher-order terms. Force fields that include higher-order dispersion interactions could resolve this issue.</div>

Download Full-text

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

10.26434/chemrxiv.5388397 ◽

2017 ◽

Author(s):

Mohamad Mohebifar ◽

Erin R. Johnson ◽

Christopher Rowley

Keyword(s):

Dipole Moment ◽

Density Functional ◽

Force Fields ◽

Mechanical Force ◽

Pharmaceutical Chemistry ◽

Dispersion Coefficients ◽

Innovative Strategy ◽

London Dispersion ◽

Improved Accuracy ◽

Mechanical Force Fields

<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>

Download Full-text

Evaluating the London Dispersion Coefficients of Protein Force Fields Using the Exchange-Hole Dipole Moment Model

10.26434/chemrxiv.6024410 ◽

2018 ◽

Author(s):

Evan T. Walters ◽

Mohamad Mohebifar ◽

Erin R. Johnson ◽

Christopher Rowley

Keyword(s):

Dipole Moment ◽

Force Fields ◽

Higher Order ◽

Side Chain ◽

Dispersion Interactions ◽

Dispersion Coefficients ◽

Hydration Energies ◽

London Dispersion ◽

Higher Order Dispersion ◽

Order Dispersion

<div>London dispersion is one of the fundamental intermolecular interactions involved in protein folding and dynamics. The popular CHARMM36, Amber ff14sb, and OPLS-</div><div>AA force fields represent these interactions through the C6 /r 6 term of the Lennard-Jones potential. The C6 parameters are assigned empirically, so these parameters are</div><div>not necessarily a realistic representation of the true dispersion interactions. In this work, dispersion coefficients of all three force fields were compared to corresponding</div><div>values from quantum-chemical calculations using the exchange-hole dipole moment (XDM) model. The force field values were found to be roughly 50% larger than the XDM values for protein backbone and side-chain models. The CHARMM36 and Amber OL15 force fields for nucleic acids were also found to exhibit this trend. To explore how these elevated dispersion coefficients affect predicted properties, the hydration energies of the side-chain models were calculated using the staged REMD-TI method of Deng and Roux for the CHARMM36, Amber ff14sb, and OPLS-AA force fields. Despite having large C 6 dispersion coefficients, these force fields predict side-chain hydration energies that are in generally good agreement with the experimental values, including for hydrocarbon residues where the dispersion component is the dominant attractive solute–solvent interaction. This suggests that these force fields predict the correct total strength of dispersion interactions, despite C6 coefficients that are considerably larger than XDM predicts. An analytical expression for the water–methane dispersion energy using XDM dispersion coefficients shows that that higher-order dispersion terms(i.e., C 8 and C 10 ) account for roughly 37.5% of the hydration energy of methane. This suggests that the C 6 dispersion coefficients used in contemporary force fields are</div><div>elevated to account for the neglected higher-order terms. Force fields that include higher-order dispersion interactions could resolve this issue.</div>

Download Full-text

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

10.26434/chemrxiv.5388397.v1 ◽

2017 ◽

Author(s):

Mohamad Mohebifar ◽

Erin R. Johnson ◽

Christopher Rowley

Keyword(s):

Dipole Moment ◽

Density Functional ◽

Force Fields ◽

Mechanical Force ◽

Pharmaceutical Chemistry ◽

Dispersion Coefficients ◽

Innovative Strategy ◽

London Dispersion ◽

Improved Accuracy ◽

Mechanical Force Fields

<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>

Download Full-text

Evaluating the London Dispersion Coefficients of Protein Force Fields Using the Exchange-Hole Dipole Moment Model

10.26434/chemrxiv.6024410.v2 ◽

2018 ◽

Author(s):

Evan T. Walters ◽

Mohamad Mohebifar ◽

Erin R. Johnson ◽

Christopher Rowley

Keyword(s):

Dipole Moment ◽

Force Fields ◽

Higher Order ◽

Side Chain ◽

Dispersion Interactions ◽

Dispersion Coefficients ◽

Hydration Energies ◽

London Dispersion ◽

Higher Order Dispersion ◽

Order Dispersion

<div>London dispersion is one of the fundamental intermolecular interactions involved in protein folding and dynamics. The popular CHARMM36, Amber ff14sb, and OPLS-</div><div>AA force fields represent these interactions through the C6 /r 6 term of the Lennard-Jones potential. The C6 parameters are assigned empirically, so these parameters are</div><div>not necessarily a realistic representation of the true dispersion interactions. In this work, dispersion coefficients of all three force fields were compared to corresponding</div><div>values from quantum-chemical calculations using the exchange-hole dipole moment (XDM) model. The force field values were found to be roughly 50% larger than the XDM values for protein backbone and side-chain models. The CHARMM36 and Amber OL15 force fields for nucleic acids were also found to exhibit this trend. To explore how these elevated dispersion coefficients affect predicted properties, the hydration energies of the side-chain models were calculated using the staged REMD-TI method of Deng and Roux for the CHARMM36, Amber ff14sb, and OPLS-AA force fields. Despite having large C 6 dispersion coefficients, these force fields predict side-chain hydration energies that are in generally good agreement with the experimental values, including for hydrocarbon residues where the dispersion component is the dominant attractive solute–solvent interaction. This suggests that these force fields predict the correct total strength of dispersion interactions, despite C6 coefficients that are considerably larger than XDM predicts. An analytical expression for the water–methane dispersion energy using XDM dispersion coefficients shows that that higher-order dispersion terms(i.e., C 8 and C 10 ) account for roughly 37.5% of the hydration energy of methane. This suggests that the C 6 dispersion coefficients used in contemporary force fields are</div><div>elevated to account for the neglected higher-order terms. Force fields that include higher-order dispersion interactions could resolve this issue.</div>

Download Full-text